METHODS FOR TREATMENT OF MULTIPLE MYELOMA USING CYCLOPROPANE CARBOXYLIC ACID {2-(Is)-(3-eTHOXY-4METHOXY-PHENYL)-2-METHANESULFONYL-ETHYL}-3-OXO-2.3-DIHYDRO-1H-ISOINDOL-4-YL}-AMIDE

ABSTRACT

Methods of treating, preventing and/or managing cancer as well as and diseases and disorders associated with, or characterized by, undesired angiogenesis are disclosed. Specific methods encompass the administration of a selective cytokine inhibitory drug alone or in combination with a second active ingredient. The invention further relates to methods of reducing or avoiding adverse side effects associated with chemotherapy, radiation therapy, hormonal therapy, biological therapy or immunotherapy which comprise the administration of a selective cytokine inhibitory drug. Pharmaceutical compositions, single unit dosage forms, and kits suitable for use in methods of the invention are also disclosed.

This application claims the benefit of U.S. provisional application Nos.60/380,842, filed May 17, 2002, and 60/424,601, filed Nov. 6, 2002, theentireties of which are incorporated herein by reference.

1. FIELD OF THE INVENTION

This invention relates to methods of treating, preventing and/ormanaging specific cancers, and other diseases including, but not limitedto, those associated with, or characterized by, undesired angiogenesis,by the administration of one or more selective cytokine inhibitory drugsalone or in combination with other therapeutics. In particular, theinvention encompasses the use of specific combinations, or “cocktails,”of drugs and other therapy, e.g., radiation to treat these specificcancers, including those refractory to conventional therapy. Theinvention also relates to pharmaceutical compositions and dosingregimens.

2. BACKGROUND OF THE INVENTION

2.1 Pathobiology of Cancer and Other Diseases

Cancer is characterized primarily by an increase in the number ofabnormal cells derived from a given normal tissue, invasion of adjacenttissues by these abnormal cells, or lymphatic or blood-borne spread ofmalignant cells to regional lymph nodes and to distant sites(metastasis). Clinical data and molecular biologic studies indicate thatcancer is a multistep process that begins with minor preneoplasticchanges, which may under certain conditions progress to neoplasia. Theneoplastic lesion may evolve clonally and develop an increasing capacityfor invasion, growth, metastasis, and heterogeneity, especially underconditions in which the neoplastic cells escape the host's immunesurveillance. Roitt, I., Brostoff, J and Kale, D., Immunology,17.1-17.12 (3rd ed., Mosby, St. Louis, Mo., 1993).

There is an enormous variety of cancers which are described in detail inthe medical literature. Examples includes cancer of the lung, colon,rectum, prostate, breast, brain, and intestine. The incidence of cancercontinues to climb as the general population ages, as new cancersdevelop, and as susceptible populations (e.g., people infected with AIDSor excessively exposed to sunlight) grow. A tremendous demand thereforeexists for new methods and compositions that can be used to treatpatients with cancer.

Many types of cancers are associated with new blood vessel formation, aprocess known as angiogenesis. Several of the mechanisms involved intumor-induced angiogenesis have been elucidated. The most direct ofthese mechanisms is the secretion by the tumor cells of cytokines withangiogenic properties. Examples of these cytokines include acidic andbasic fibroblastic growth factor (a,b-FGF), angiogenin, vascularendothelial growth factor (VEGF), and TNF-α. Alternatively, tumor cellscan release angiogenic peptides through the production of proteases andthe subsequent breakdown of the extracellular matrix where somecytokines are stored (e.g., b-FGF). Angiogenesis can also be inducedindirectly through the recruitment of inflammatory cells (particularlymacrophages) and their subsequent release of angiogenic cytokines (e.g.,TNF-α, bFGF).

A variety of other diseases and disorders are also associated with, orcharacterized by, undesired angiogenesis. For example, enhanced orunregulated angiogenesis has been implicated in a number of diseases andmedical conditions including, but not limited to, ocular neovasculardiseases, choroidal neovascular diseases, retina neovascular diseases,rubeosis (neovascularization of the angle), viral diseases, geneticdiseases, inflammatory diseases, allergic diseases, and autoimmunediseases. Examples of such diseases and conditions include, but are notlimited to: diabetic retinopathy, retinopathy of prematurity; cornealgraft rejection; neovascular glaucoma; retrolental fibroplasia; andproliferative vitreoretinopathy.

Accordingly, compounds that can control angiogenesis or inhibit theproduction of certain cytokines, including TNF-α, may be useful in thetreatment and prevention of various diseases and conditions.

2.2 Methods of Treatment

Current cancer therapy may involve surgery, chemotherapy, hormonaltherapy and/or radiation treatment to eradicate neoplastic cells in apatient (see, for example, Stockdale, 1998, Medicine, vol. 3, Rubensteinand Federman, eds., Chapter 12, Section IV). Recently, cancer therapycould also involve biological therapy or immunotherapy. All of theseapproaches pose significant drawbacks for the patient. Surgery, forexample, may be contraindicated due to the health of a patient or may beunacceptable to the patient. Additionally, surgery may not completelyremove neoplastic tissue. Radiation therapy is only effective when theneoplastic tissue exhibits a higher sensitivity to radiation than normaltissue. Radiation therapy can also often elicit serious side effects.Hormonal therapy is rarely given as a single agent. Although hormonaltherapy can be effective, it is often used to prevent or delayrecurrence of cancer after other treatments have removed the majority ofcancer cells. Biological therapies and immunotherapies are limited innumber and may produce side effects such as rashes or swellings,flu-like symptoms, including fever, chills and fatigue, digestive tractproblems or allergic reactions.

With respect to chemotherapy, there are a variety of chemotherapeuticagents available for treatment of cancer. A majority of cancerchemotherapeutics act by inhibiting DNA synthesis, either directly, orindirectly by inhibiting the biosynthesis of deoxyribonucleotidetriphosphate precursors, to prevent DNA replication and concomitant celldivision. Gilman et al., Goodman and Gilman's: The Pharmacological Basisof Therapeutics, Tenth Ed. (McGraw Hill, New York).

Despite availability of a variety of chemotherapeutic agents,chemotherapy has many drawbacks. Stockdale, Medicine, vol. 3, Rubensteinand Federman, eds., ch. 12, sect. 10, 1998. Almost all chemotherapeuticagents are toxic, and chemotherapy causes significant, and oftendangerous side effects including severe nausea, bone marrow depression,and immunosuppression. Additionally, even with administration ofcombinations of chemotherapeutic agents, many tumor cells are resistantor develop resistance to the chemotherapeutic agents. In fact, thosecells resistant to the particular chemotherapeutic agents used in thetreatment protocol often prove to be resistant to other drugs, even ifthose agents act by different mechanism from those of the drugs used inthe specific treatment. This phenomenon is referred to as pleiotropicdrug or multidrug resistance. Because of the drug resistance, manycancers prove refractory to standard chemotherapeutic treatmentprotocols.

Other diseases or conditions associated with, or characterized by,undesired angiogenesis are also difficult to treat. However, somecompounds such as protamine, hepain and steroids have been proposed tobe useful in the treatment of certain specific diseases. Taylor et al.,Nature 297:307 (1982); Folkman et al., Science 221:719 (1983); and U.S.Pat. Nos. 5,001,116 and 4,994,443. Thalidomide and certain derivativesof it have also been proposed for the treatment of such diseases andconditions. U.S. Pat. Nos. 5,593,990, 5,629,327, 5,712,291, 6,071,948and 6,114,355 to D'Amato.

Still, there is a significant need for safe and effective methods oftreating, preventing and managing cancer and other diseases andconditions, particularly for diseases that are refractory to standardtreatments, such as surgery, radiation therapy, chemotherapy andhormonal therapy, while reducing or avoiding the toxicities and/or sideeffects associated with the conventional therapies.

2.3 Selective Cytokine Inhibitory Drugs

Compounds referred to as SelCIDs™ (Celgene Corporation) or SelectiveCytokine Inhibitory Drugs have been synthesized and tested. Thesecompounds potently inhibit TNF-α production, but exhibit modestinhibitory effects on LPS induced IL1β and IL12, and do not inhibit IL6even at high drug concentrations. In addition, SelCIDs™ tend to producea modest IL10 stimulation. L. G. Corral, et al. Ann. Rheum. Dis.58:(Suppl I) 1107-1113 (1999).

Further characterization of the selective cytokine inhibitory drugsshows that they are potent PDE4 inhibitors. PDE4 is one of the majorphosphodiesterase isoenzymes found in human myeloid and lymphoid lineagecells. The enzyme plays a crucial part in regulating cellular activityby degrading the ubiquitous second messenger cAMP and maintaining it atlow intracellular levels. Id. Inhibition of PDE4 activity results inincreased cAMP levels leading to the modulation of ILPS inducedcytokines including inhibition of TNF-α production in monocytes as wellas in lymphocytes.

3. SUMMARY OF THE INVENTION

This invention encompasses methods of treating and preventing certaintypes of cancer, including primary and metastatic cancer, as well ascancers that are refractory or resistant to conventional chemotherapy.The methods comprise administering to a patient in need of suchtreatment or prevention a therapeutically or prophylactically effectiveamount of a selective cytokine inhibitory drug, or a pharmaceuticallyacceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrugthereof. The invention also encompasses methods of managing certaincancers (e.g., preventing or prolonging their recurrence, or lengtheningthe time of remission) which comprise administering to a patient in needof such management a prophylactically effective amount of a selectivecytokine inhibitory drug of the invention, or a pharmaceuticallyacceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrugthereof.

In particular methods of the invention, a selective cytokine inhibitorydrug is administered in combination with a therapy conventionally usedto treat, prevent or manage cancer. Examples of such conventionaltherapies include, but are not limited to, surgery, chemotherapy,radiation therapy, hormonal therapy, biological therapy andimmunotherapy.

This invention also encompasses methods of treating, managing orpreventing diseases and disorders other than cancer that are associatedwith, or characterized by, undesired angiogenesis, which compriseadministering to a patient in need of such treatment, management orprevention a therapeutically or prophylactically effective amount of aselective cytokine inhibitory drug, or a pharmaceutically acceptablesalt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof.

In other methods of the invention, a selective cytokine inhibitory drugis administered in combination with a therapy conventionally used totreat, prevent or manage diseases or disorders associated with, orcharacterized by, undesired angiogenesis. Examples of such conventionaltherapies include, but are not limited to, surgery, chemotherapy,radiation therapy, hormonal therapy, biological therapy andimmunotherapy.

This invention encompasses pharmaceutical compositions, single unitdosage forms, dosing regimens and kits which comprise a selectivecytokine inhibitory drug, or a pharmaceutically acceptable salt,solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, and asecond, or additional, active agent. Second active agents includespecific combinations, or “cocktails,” of drugs.

4. DETAILED DESCRIPTION OF THE INVENTION

A first embodiment of the invention encompasses methods of treating,managing, or preventing cancer which comprises administering to apatient in need of such treatment or prevention a therapeutically orprophylactically effective amount of a selective cytokine inhibitorydrug of the invention, or a pharmaceutically acceptable salt, solvate,hydrate, stereoisomer, clathrate, or prodrug thereof.

In particular methods encompassed by this embodiment, the selectivecytokine inhibitory drug is administered in combination with anotherdrug (“second active agent”) or method of treating, managing, orpreventing cancer. Second active agents include small molecules andlarge molecules (e.g., proteins and antibodies), examples of which areprovided herein, as well as stem cells. Methods, or therapies, that canbe used in combination with the administration of the selective cytokineinhibitory drug include, but are not limited to, surgery, bloodtransfusions, immunotherapy, biological therapy, radiation therapy, andother non-drug based therapies presently used to treat, prevent ormanage cancer.

Another embodiment of the invention encompasses methods of treating,managing or preventing diseases and disorders other than cancer that arecharacterized by undesired angiogenesis. These methods comprise theadministration of a therapeutically or prophylactically effective amountof a selective cytokine inhibitory drug, or a pharmaceuticallyacceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrugthereof.

Examples of diseases and disorders associated with, or characterized by,undesired angiogenesis include, but are not limited to, inflammatorydiseases, autoimmune diseases, viral diseases, genetic diseases,allergic diseases, bacterial diseases, ocular neovascular diseases,choroidal neovascular diseases, retina neovascular diseases, andrubeosis (neovascularization of the angle).

In particular methods encompassed by this embodiment, the selectivecytokine inhibitory drug is administer in combination with a secondactive agent or method of treating, managing, or preventing the diseaseor condition. Second active agents include small molecules and largemolecules (e.g., proteins and antibodies), examples of which areprovided herein, as well as stem cells. Methods, or therapies, that canbe used in combination with the administration of the selective cytokineinhibitory drug include, but are not limited to, surgery, bloodtransfusions, immunotherapy, biological therapy, radiation therapy, andother non-drug based therapies presently used to treat, prevent ormanage disease and conditions associated with, or characterized by,undesired angiogenesis.

The invention also encompasses pharmaceutical compositions (e.g., singleunit dosage forms) that can be used in methods disclosed herein.Particular pharmaceutical compositions comprise a selective cytokineinhibitory drug of the invention, or a pharmaceutically acceptable salt,solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, and asecond active agent.

4.1 Selective Cytokine Inhibitory Drugs

Compounds used in the invention include racemic, stereomerically pure orstereomerically enriched selective cytokine inhibitory drugs,stereomerically or enantiomerically pure compounds that have selectivecytokine inhibitory activities, and pharmaceutically acceptable salts,solvates, hydrates, stereoisomers, clathrates, and prodrugs thereof.Preferred compounds used in the invention are known Selective CytokineInhibitory Drugs (SelCIDs™) of Celgene Corporation.

As used herein and unless otherwise indicated, the terms “selectivecytokine inhibitory drug” and “SelCIDs™” encompass small molecule drugs,e.g., small organic molecules which are not peptides, proteins, nucleicacids, oligosaccharides or other macromolecules. Preferred compoundsinhibit TNF-α production. Further, the compounds may also have a modestinhibitory effect on LPS induced IL1β and IL12. More preferably, thecompounds of the invention are potent PDE4 inhibitors. PDE4 is one ofthe major phosphodiesterase isoenzymes found in human myeloid andlymphoid lineage cells. The enzyme plays a crucial part in regulatingcellular activity by degrading the ubiquitous second messenger cAMP andmaintaining it at low intracellular levels. Without being limited bytheory, inhibition of PDE4 activity results in increased cAMP levelsleading to the modulation of LPS induced cytokines, including inhibitionof TNF-α production in monocytes as well as in lymphocytes.

Specific examples of selective cytokine inhibitory drugs include, butare not limited to, the cyclic imides disclosed in U.S. Pat. No.5,605,914; the cycloalkyl amides and cycloalkyl nitriles of U.S. Pat.Nos. 5,728,844 and 5,728,845, respectively, the aryl amides (forexample, an embodiment beingN-benzoyl-3-amino-3-(3′,4′-dimethoxyphenyl)-propanamide) of U.S. Pat.Nos. 5,801,195 and 5,736,570; the imide/amide ethers and alcohols (forexample, 3-phthalimido-3-(3′,4′-dimethoxypheryl)propan-1-ol) disclosedin U.S. Pat. No. 5,703,098; the succinimides and maleimides (for examplemethyl3-(3′,4′,5′6′-petrahydrophthalimdo)-3-(3″,4″-dimethoxyphenyl)propionate)disclosed in U.S. Pat. No. 5,658,940; imido and amido substitutedalkanohydroxamic acids disclosed in WO 99/06041 and substitutedphenethylsulfones disclosed in U.S. Pat. No. 6,020,358; and aryl amidessuch as N-benzoyl-3-amino-3-(3′,4′-dimethoxyphenyl)propanamide asdescribed in U.S. Pat. No. 6,046,221. The entireties of each of thepatents and patent applications identified herein are incorporatedherein by reference.

Additional selective cytokine inhibitory drugs belong to a family ofsynthesized chemical compounds of which typical embodiments include3-(1,3-dioxobenzo-[f]isoindol-2-yl)-3-(3-cyclopentyloxy-4-methoxyphenyl)propionamideand3-(1,3-dioxo-4-azaisoindol-2-yl)-3-(3,4-dimethoxyphenyl)-propionamide.

Other specific selective cytokine inhibitory drugs belong to a class ofnon-polypeptide cyclic amides disclosed in U.S. Pat. Nos. 5,698,579 and5,877,200, both of which are incorporated herein. Representative cyclicamides include compounds of the formula:

wherein n has a value of 1, 2, or 3;

R⁵ is o-phenylene, unsubstituted or substituted with 1 to 4 substituentseach selected independently from the group consisting of nitro, cyano,trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl,carbamoyl, acetoxy, carboxy, hydroxy, amino, alkylamino, dialkylamino,acylamino, alkyl of 1 to 10 carbon atoms, alkyl of 1 to 10 carbon atoms,and halo;

R⁷ is (i) phenyl or phenyl substituted with one or more substituentseach selected independently of the other from the group consisting ofnitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy,acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl of 1 to 10carbon atoms, alkoxy of 1 to 10 carbon atoms, and halo, (ii) benzylunsubstituted or substituted with 1 to 3 substituents selected from thegroup consisting of nitro, cyano, trifluoromethyl, carbothoxy,carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy,hydroxy, amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbonatoms, and halo, (iii) naphthyl, and (iv) benzyloxy;

R¹² is —OH, alkoxy of 1 to 12 carbon atoms, or

R⁸ is hydrogen or alkyl of 1 to 10 carbon atoms; and

R⁹ is hydrogen, alkyl of 1 to 10 carbon atoms, —COR¹⁰, or —SO₂R¹⁰,wherein R¹⁰ is hydrogen, alkyl of 1 to 10 carbon atoms, or phenyl.

Specific compounds of this class include, but are not limited to:

-   3-phenyl-2-(1-oxoisoindolin-2-yl)propionic acid;-   3-phenyl-2-(1-oxoisoindolin-2-yl)propionamide;-   3-phenyl-3-(1-oxoisoindolin-2-yl)propionic acid;-   3-phenyl-3-(1-oxoisoindolin-2-yl)propionamide;-   3-(4-methoxyphenyl)-3-(1-oxisoindolin-yl)propionic acid;-   3-(4-methoxyphenyl)-3-(1-oxisoindolin-yl)propionamide;-   3-(3,4-dimethoxyphenyl)-3-(1-oxisoindolin-2-yl)propionic acid;-   3-(3,4-dimethoxy-phenyl)-3-(1-oxo-1,3-dihydroisoindol-2-yl)-propionamide;-   3-(3,4-dimethoxyphenyl)-3-(1-oxisoindolin-2-yl)propionamide;-   3-(3,4-diethoxyphenyl)-3-(1-oxoisoindolin-yl)propionic acid;-   methyl    3-(1-oxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate;-   3-(1-oxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionic acid;-   3-(1-oxoisoindolin-2-yl)-3-(3-propoxy-4-methoxyphenyl)propionic    acid;-   3-(1-oxoisoindolin-2-yl)-3-(3-butoxy-4-methoxyphenyl)propionic acid;-   3-(1-oxoisoindolin-2-yl)-3-(3-propoxy-4-methoxyphenyl)propionamide;-   3-(1-oxoisoindolin-2-yl)-3-(3-butoxy-4-methoxyphenyl)propionamide;-   methyl    3-(1-oxoisoindolin-2-yl)-3-(3-butoxy-4-methoxyphenyl)propionate; and-   methyl    3-(1-oxoisoindolin-2-yl)-3-(3-propoxy-4-methoxyphenyl)propionate.

Other specific selective cytokine inhibitory drugs include the imido andamido substituted alkanohydroxamic acids disclosed in WO 99/06041, whichis incorporated herein by reference. Examples of such compound include,but are not limited to:

wherein each of R¹ and R², when taken independently of each other, ishydrogen, lower alkyl, or R¹ and R², when taken together with thedepicted carbon atoms to which each is bound, is o-phenylene,o-naphthylene, or cyclohexene-1,2-diyl, unsubstituted or substitutedwith 1 to 4 substituents each selected independently from the groupconsisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy,carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino,alkylamino, dialkylamino, acylamino, alkyl of 1 to 10 carbon atoms,alkoxy of 1 to 10 carbon atoms, and halo;

R³ is phenyl substituted with from one to four substituents selectedfrom the group consisting of nitro, cyano, trifluoromethyl, carbethoxy,carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy,hydroxy, amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbonatoms, alkylthio of 1 to 10 carbon atoms, benzyloxy, cycloalkoxy of 3 to6 carbon atoms, C₄-C₆-cycloalkylidenemethyl, C₃-C₁₀-alkylidenemethyl,indanyloxy, and halo;

R⁴ is hydrogen, alkyl of 1 to 6 carbon atoms, phenyl, or benzyl;

R^(4′) is hydrogen or alkyl of 1 to 6 carbon atoms;

R⁵ is —CH₂—, —CH₂—CO—, —SO₂—, —S—, or —NHCO—;

n has a value of 0, 1, or 2; and

the acid addition salts of said compounds which contain a nitrogen atomcapable of being protonated.

Additional specific selective cytokine inhibitory drugs used in theinvention include, but are not limited to:

-   3-(3-ethoxy-4-methoxyphenyl)-N-hydroxy-3-(1-oxoisoindolinyl)propionamide;-   3-(3-ethoxy-4-methoxyphenyl)-N-methoxy-3-(1-oxoisoindolinyl)propionamide;-   N-benzyloxy-3-(3-ethoxy-4-methoxyphenyl)-3-phthalimidopropionamide;-   N-benzyloxy-3-(3-ethoxy-4-methoxyphenyl)-3-(3-nitrophthalimido)propionamide;-   N-benzyloxy-3-(3-ethoxy-4-methoxyphenyl)-3-(1-oxoisoindolinyl)propionamide;-   3-(3-ethoxy-4-methoxyphenyl)-N-hydroxy-3-phthalimidopropionamide;-   N-hydroxy-3-(3,4-dimethoxyphenyl)-3-phthalimidopropionamide;-   3-(3-ethoxy-4-methoxyphenyl)-N-hydroxy-3-(3-nitrophthalimido)propionamide;-   N-hydroxy-3-(3,4-dimethoxyphenyl)-3-(1-oxoisoindolinyl)propionamide;-   3-(3-ethoxy-4-methoxyphenyl)-N-hydroxy-3-(4-methyl-phthalimido)propionamide;-   3-(3-cyclopentyloxy-4-methoxyphenyl)-N-hydroxy-3-phthalimidopropionamide;-   3-(3-ethoxy-4-methoxyphenyl)-N-hydroxy-3-(1,3-dioxo-2,3-dihydro-1H-benzo[f]isoindol-2-yl)propionamide;-   N-hydroxy-3-{3-(2-propoxy)-4-methoxyphenyl}-3-phthalimidopropionamide;-   3-(3-ethoxy-4-methoxyphenyl)-3-(3,6-difluorophthalimido)-N-hydroxypropionamide;-   3-(4-aminophthalimido)-3-(3-ethoxy-4-methoxyphenyl)-N-hydroxypropionamide;-   3-(3-aminophthalimido)-3-(3-ethoxy-4-methoxyphenyl)-N-hydroxypropionamide;-   N-hydroxy-3-(3,4-dimethoxyphenyl)-3-(1-oxoisoindolinyl)propionamide;-   3-(3-cyclopentyloxy-4-methoxyphenyl)-N-hydroxy-3-(1-oxoisoindolinyl)    propionamide; and-   N-benzyloxy-3-(3-ethoxy-4-methoxyphenyl)-3-(3-nitrophthalimido)propionamide.

Additional selective cytokine inhibitory drugs used in the inventioninclude the substituted phenethylsulfones substituted on the phenylgroup with a oxoisoindine group. Examples of such compounds include, butare not limited to, those disclosed in U.S. Pat. No. 6,020,358, which isincorporated herein, which include the following:

wherein the carbon atom designated * constitutes a center of chirality;

Y is C═O, CH2, SO₂, or CH₂C═O; each of R¹, R², R³, and R⁴, independentlyof the others, is hydrogen, halo, alkyl of 1 to 4 carbon atoms, alkoxyof 1 to 4 carbon atoms, nitro, cyano, hydroxy, or —NR⁸R⁹; or any two ofR¹, R², R³, and R⁴ on adjacent carbon atoms, together with the depictedphenylene ring are naphthylidene;

each of R⁵ and R⁶, independently of the other, is hydrogen, alkyl of 1to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, cyano, or cycloalkoxyof up to 18 carbon atoms;

R⁷ is hydroxy, alkyl of 1 to 8 carbon atoms, phenyl, benzyl, orNR^(8′)R^(9′);

each of R⁸ and R⁹ taken independently of the other is hydrogen, alkyl of1 to 8 carbon atoms, phenyl, or benzyl, or one of R⁸ and R⁹ is hydrogenand the other is —COR¹⁰ or —SO₂R¹⁰, or R⁸ and R⁹ taken together aretetramethylene, pentamethylene, hexamethylene, or —CH₂CH₂X¹CH₂CH₂— inwhich X¹ is —O—, —S— or —NH—; and

each of R^(8′) and R^(9′) taken independently of the other is hydrogen,alkyl of 1 to 8 carbon atoms, phenyl, or benzyl, or one of R⁸ and R⁹ ishydrogen and the other is —COR^(10′) or —SO₂R^(10′), or R^(8′) andR^(9′) taken together are tetramethylene, pentamethylene, hexamethylene,or —CH₂CH₂X²CH₂CH₂— in which X² is —O—, —S—, or —NH—.

It will be appreciated that while for convenience the above compoundsare identified as phenethylsulfones, they include sulfonamides when R⁷is NR^(8′)R^(9′).

Specific groups of such compounds are those in which Y is C═O or CH₂.

A further specific group of such compounds are those in which each ofR¹, R², R³, and R⁴ independently of the others, is hydrogen, halo,methyl, ethyl, methoxy, ethoxy, nitro, cyano, hydroxy, or —NR⁸R⁹ inwhich each of R⁸ and R⁹ taken independently of the other is hydrogen ormethyl or one of R⁸ and R⁹ is hydrogen and the other is —COCH₃.

Particular compounds are those in which one of R¹, R², R³, and R⁴ is—NH₂ and the remaining of R¹, R², R³, and R⁴ are hydrogen.

Particular compounds are those in which one of R¹, R², R³, and R⁴ is—NHCOCH₃ and the remaining of R¹, R², R³, and R⁴ are hydrogen.

Particular compounds are those in which one of R¹, R², R³, and R⁴ is—N(CH₃)₂ and the remaining of R¹, R², R³, and R⁴ are hydrogen.

A further preferred group of such compounds are those in which one ofR¹, R², R³, and R⁴ is methyl and the remaining of R¹, R², R³, and R⁴ arehydrogen.

Particular compounds are those in which one of R¹, R², R³, and R⁴ isfluoro and the remaining of R¹, R², R³, and R⁴ are hydrogen.

Particular compounds are those in which each of R⁵ and R⁶, independentlyof the other, is hydrogen, methyl, ethyl, propyl, methoxy, ethoxy,propoxy, cyclopentoxy, or cyclohexoxy.

Particular compounds are those in which R⁵ is methoxy and R⁶ ismonocycloalkoxy, polycycloalkoxy, and benzocycloalkoxy.

Particular compounds are those in which R⁵ is methoxy and R⁶ is ethoxy.

Particular compounds are those in which R⁷ is hydroxy, methyl, ethyl,phenyl, benzyl, or NR^(8′)R^(9′) in which each of R^(8′) and R^(9′)taken independently of the other is hydrogen or methyl.

Particular compounds are those in which R⁷ is methyl, ethyl, phenyl,benzyl or NR^(8′)R^(9′) in which each of R^(8′) and R^(9′) takenindependently of the other is hydrogen or methyl.

Particular compounds are those in which R⁷ is methyl.

Particular compounds are those in which R⁷ is NR^(8′)R^(9′) in whicheach of R^(8′) and R^(9′) taken independently of the other is hydrogenor methyl.

Other specific selective cytokine inhibitory drugs includefluoroalkoxy-substituted 1,3-dihydro-isoindolyl compounds found in U.S.Provisional Application No. 60/436,975 to G. Muller et al., filed Dec.30, 2002, which is incorporated herein in its entirety by reference.Representative fluoroalkoxy-substituted 1,3-dihydro-isoindolyl compoundsinclude compounds of the formula:

wherein:

Y is —C(O)—, —CH₂, —CH₂C(O)—, —C(O)CH₂—, or SO₂;

Z is —H, —C(O)R³, —(C₀₋₁-alkyl)-SO₂—(C₁₋₄-alkyl), —C₁₋₈-alkyl, —CH₂OH,CH₂(O)(C₁₋₈-alkyl) or —CN;

R₁ and R₂ are each independently —CHF₂, —C₁₋₈-alkyl, —C₃₋₁₈-cycloalkyl,or —(C₁₋₁₀-alkyl)(C₃₋₁₈-cycloalkyl), and at least one of R₁ and R₂ isCHF₂;

R³ is —NR⁴R⁵, -alkyl, —OH, —O-alkyl, phenyl, benzyl substituted phenyl,or substituted benzyl;

R⁴ and R⁵ are each independently —H, —C₁₋₈-alkyl, —OH, —OC(O)R⁶;

R⁶ is —C₁₋₈-alkyl, -amino(C₁₋₈-alkyl), -phenyl, -benzyl, or -aryl;

X₁, X₂, X₃, and X₄ are each independent —H, -halogen, -nitro, —NH₂,—CF₃, —C₁₋₆-alkyl, —(C₀₋₄-alkyl)-(C₃₋₆-cycloalkyl), (C₀₋₄-alkyl)-NR⁷R⁸,(C₀₋₄-alkyl)-N(H)C(O)—(R⁸), (C₀₋₄-alkyl)-N(H)C(O)N(R⁷R⁸),(C₀₋₄-alkyl)-N(H)C(O)O(R⁷R⁸), (C₀₋₄-alkyl)-OR⁸, (C₀₋₄-alkyl)-imidazolyl,(C₀₋₄-alkyl)-pyrrolyl, (C₀₋₄-alkyl)-oxadiazolyl, or(C₀₋₄-alkyl)-triazolyl, or two of X₁, X₂, X₃, and X₄ may be joinedtogether to form a cycloalkyl or heterocycloalkyl ring, (e.g., X₁ andX₂, X₂ and X₃, X₃ and X₄, X₁ and X₃, X₂ and X₄, or X₁ and X₄ may form a3, 4, 5, 6, or 7 membered ring which may be aromatic, thereby forming abicyclic system with the isoindolyl ring); and

R⁷ and R⁸ are each independently H, C₁₋₉-alkyl, C₃₋₆-cycloalkyl,(C₁₋₆-alkyl)-(C₃₋₆-cycloalkyl), (C₁₋₆-alkyl)-N(R⁷R⁸), (C₁₋₆-alkyl)-OR⁸,phenyl, benzyl, or aryl;

or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer,clathrate, or prodrug thereof.

Specific compounds include, but are not limited to:

-   3-(4-Acetylamino-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-propionic    acid;-   3-(4-Acetylamino-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-N,N-dimethyl-propionamide;-   3-(4-Acetylamino-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-(3    cyclopropylmethoxy-4-difluoromethoxy-phenyl)-propionamide;-   3-(3-Cyclopropylmethoxy-4-difluoromethoxy-phenyl)-3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-propionic    acid;-   3-(3-Cyclopropylmethoxy-4-difluoromethoxy-phenyl)-3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-N-hydroxy-propionamide;-   3-(3-Cyclopropylmethoxy-4-difluoromethoxy-phenyl)-3-(7-nitro-1-oxo-1,3-dihydro-isoindol-2-yl)-propionic    acid methyl ester;-   3-(3-Cyclopropylmethoxy-4-difluoromethoxy-phenyl)-3-(7-nitro-1-oxo-1,3-dihydro-isoindol-2-yl)-propionic    acid;-   3-(3-Cyclopropylmethoxy-4-difluoromethoxy-phenyl-3-(7-nitro-1-oxo-1,3-dihydro-isoindol-2-yl)-)-N,N-dimethyl-propionamide;-   3-(7-Amino-1-oxo-1,3-dihydro-isoindol-2-yl)-3-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-N,N-dimethyl-propionamide;-   3-(4-Difluoromethoxy-3-ethoxy-phenyl)-3-(7-nitro-1-oxo-1,3-dihydro-isoindol-2-yl)-propionic    acid methyl ester;-   3-(7-Amino-1-oxo-1,3-dihydro-isoindol-2-yl)-3-(4-difluoromethoxy-3-ethoxy-phenyl)-propionic    acid methyl ester;-   3-[7-(Cyclopropanecarbonyl-amino)-1-oxo-1,3-dihydro-isoindol-2-yl]-3-(4-difluoromethoxy-3-ethoxy-phenyl)-propionic    acid methyl ester;-   3-(7-Acetylamino-1-oxo-1,3-dihydro-isoindol-2-yl)-3-(4-difluoromethoxy-3-ethoxy-phenyl)-propionic    acid methyl ester,-   3-(7-Acetylamino-1-oxo-1,3-dihydro-isoindol-2-yl)-3-(4-difluoromethoxy-3-ethoxy-phenyl)-propionic    acid;-   3-[7-(Cyclopropanecarbonyl-amino)-1-oxo-1,3-dihydro-isoindol-2-yl]-3-(4-difluoromethoxy-3-ethoxy-phenyl)-propionic    acid;-   Cyclopropanecarboxylic acid    {2-[2-carbamoyl-1-(4-difluoromethoxy-3-ethoxy-phenyl)-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide;-   Cyclopropanecarboxylic acid    {2-[1-(4-difluoromethoxy-3-ethoxy-phenyl)-2-dimethylcarbamoyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-;-   Cyclopropanecarboxylic acid    {2-[(1-(4-difluoromethoxy-3-ethoxy-phenyl)-2-hydroxycarbamoyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide;-   3-(7-Acetylamino-1-oxo-1,3-dihydro-isoindol-2-yl)-3-(4-difluoromethoxy-3-ethoxy-phenyl)-propionamide;-   3-(7-Acetylamino-1-oxo-1,3-dihydro-isoindol-2-yl)-3-(4-difluoromethoxy-3-ethoxy-phenyl)-N,N-dimethyl-propionamide;-   3-(7-Acetylamino-1-oxo-1,3-dihydro-isoindol-2-yl)-3-(4-difluoromethoxy-3-ethoxy-phenyl)-N-hydroxy-propionamide;-   3-(4-Acetylamino-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-(4-difluoromethoxy-3-ethoxy-phenyl)-propionic    acid;-   3-(4-Acetylamino-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-(4-difluoromethoxy-3-ethoxy-phenyl)-propionamide;-   3-(4-Acetylamino-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-(4-difluoromethoxy-3-ethoxy-phenyl)-N,N-dimethyl-propionamide;-   3-(4-Acetylamino-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-(4-difluoromethoxy-3-ethoxy-phenyl)-N-hydroxy-propionamide;-   Cyclopropanecarboxylic acid    {2-[1-(4-difluoromethoxy-3-ethoxy-phenyl)-2-methanesulfonyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide;-   N-{2-[1-(4-Difluoromethoxy-3-ethoxy-phenyl)-2-methanesulfonyl-ethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}-acetamide;    and-   Cyclopropanecarboxylic acid    {2-[2-carbamoyl-1-(4-difluoromethoxy-3-ethoxy-phenyl)-ethyl]-7-chloro-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide.

Other selective cytokine inhibitory drugs include 7-amido-substitutedisoindolyl compounds found in U.S. Provisional Application No.60/454,155 to G. Muller et al., filed Mar. 12, 2003, which isincorporated herein in its entirety by reference. Representative7-amido-substituted isoindolyl compounds include compounds of theformula:

wherein:

Y is —C(O)—, —CH₂, —CH₂C(O)— or SO₂;

X is H;

Z is (C₀₋₄-alkyl)-C(O)R³, C₁₋₄-alkyl, (C₀₋₄-alkyl)-OH,(C₁₋₄-alkyl)-O(C₁₋₄-alkyl), (C₁₋₄-alkyl)-SO₂(C₁₋₄-alkyl),(C₀₋₄-alkyl)-SO(C₁₋₄-alkyl), (C₀₋₄-alkyl)-NH₂,(C₀₋₄-alkyl)-N(C₁₋₈-alkyl)₂, (C₀₋₄-alkyl)-N(H)(OH), CH₂NSO₂(C₁₋₄-alkyl);

R₁ and R₂ are independently C₁₋₈-alkyl, cycloalkyl, or(C₁₋₄-alkyl)cycloalkyl;

R³ is, NR⁴R⁵, OH, or O—(C₁₋₈-alkyl);

R⁴ is H;

R⁵ is —OH, or —OC(O)R⁶;

R⁶ is C₁₋₈-alkyl, amino-(C₁₋₈-alkyl), (C₁₋₈-alkyl)-(C₃₋₆-cycloalkyl),C₃₋₆cycloalkyl, phenyl, benzyl, or aryl;

or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer,clathrate, or prodrug thereof; or the formula:

wherein:

Y is —C(O)—, —CH₂, —CH₂C(O)—, or SO₂;

X is halogen, —CN, —NR₇R₈, —NO₂, or CF₃,

W is

Z is (C₀₋₄-alkyl)-SO₂(C₁₋₄-alkyl), —(C₀₋₄alkyl)-CN, —(C₀₋₄alkyl)-C(O)R³,C₁₋₄-alkyl, (C₀₋₄-alkyl)OH, (C₀₋₄-alkyl)O(C₁₋₄-alkyl),(C₀₋₄-alkyl)SO(C₁₋₄-alkyl), (C₀₋₄-alkyl)NH₂, (C₀₋₄-alkyl)N(C₁₋₈-alkyl)₂,(C₀₋₄-alkyl)N(H)(OH), or (C₀₋₄-alkyl)NSO₂(C₁₋₄-alkyl);

W is —C₃₋₆-cycloalkyl, —(C₁₋₈-alkyl)-(C₃₋₆-cycloalkyl),—(C₀₋₈-alkyl)-(C₃₋₆cycloalkyl)-NR₇R₈, (C₀₋₈-alkyl)-NR₇R₈,(C₀₋₄-alkyl)-CHR₉—(Co-alkyl)-NR₇R₈;

R₁ and R₂ are independently C₁₋₈-alkyl, cycloalkyl, or(C₁₋₄-alkyl)cycloalkyl;

R³ is C₁₋₈-alkyl, NR⁴R⁵, OH, or O—(C₁₋₈-alkyl);

R⁴ and R⁵ are independently H, C₁₋₈-alkyl,(C₀₋₈-alkyl)-(C₃₋₆-cycloalkyl), OH, or —OC(O)R⁶;

R⁶ is C₁₋₈-alkyl, (C₀₋₈-alkyl)-(C₃₋₆-cycloalkyl), amino-(C₁₋₈-alkyl),phenyl, benzyl, or aryl;

R₇ and R₈ are each independently H, C₁₋₈-alkyl,(C₀₋₈alkyl)-(C₃₋₆-cycloalkyl), phenyl, benzyl, aryl, or can be takentogether with the atom connecting them to form a 3 to 7 memberedheterocycloalkyl or heteroaryl ring;

R₉ is C₁₋₄-alkyl, (C₀₋₄-alkyl)aryl, (C₀₋₄-alkyl)-(C₃₋₆-cycloalkyl),(C₀₋₄-alkyl)-heterocylcle;

or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer,clathrate, or prodrug thereof.

Still other selective cytokine inhibitory drugs includeN-alkyl-hydroxamic acid-isoindolyl compounds found in U.S. ProvisionalApplication No. 60/454,149 to G. Muller et al., filed Mar. 12, 2003,which is incorporated herein in its entirety by reference.Representative N-alkyl-hydroxamic acid-isoindolyl compounds includecompounds of the formula:

wherein:

Y is —C(O)—, —CH₂, —CH₂C(O)— or SO₂;

R₁ and R₂ are independently C₁₋₈-alkyl, CF₂H, CF₃, CH₂CHF₂, cycloalkyl,or (C₁₋₈-alkyl)cycloalkyl;

Z₁ is H, C₁₋₆-alkyl, —NH₂—NR₃R₄ or OR₅;

Z₂ is H or C(O)R₅;

X₁, X₂, X₃ and X₄ are each independent H, halogen, NO₂, OR₃, CF₃,C₁₋₆-alkyl, (C₀₋₄-alkyl)-(C₃₋₆-cycloalkyl), (C₀₋₄-alkyl)-N—(R₈R₉),(C₀₋₄-alkyl)-NHC(O)—(R₈), (C₀₋₄-alkyl)-NHC(O)CH(R₈)(R₉),(C₀₋₄-alkyl)-NHC(O)N(R₈R₉), (C₀₋₄-alkyl)-NHC(O)O(R₈), (C₀₋₄-alkyl)-O—R₈,(C₀₋₄-alkyl)-imidazolyl, (C₀₋₄-alkyl)-pyrrolyl,(C₀₋₄-alkyl)-oxadiazolyl, (C₀₋₄-alkyl)-triazolyl or(C₀₋₄-alkyl)-heterocycle;

R₃, R₄, and R₅ are each independently H, C₁₋₆-alkyl, O—C₁₋₆-alkyl,phenyl, benzyl, or aryl;

R₆ and R₇ are independently H or C₁₋₆-alkyl;

R₈ and R₉ are each independently H, C₁₋₉-alkyl, C₃₋₆-cycloalkyl,(C₁₋₆-alkyl)-(C₃₋₆-cycloalkyl), (C₀₋₆-alkyl)-N(R₄R₅), (C₁₋₆-alkyl)-OR₅,phenyl, benzyl, aryl, piperidinyl, piperizinyl, pyrrolidinyl,morpholino, or C₃₋₇-heterocycloalkyl; or

a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer,clathrate, or prodrug thereof.

Specific selective cytokine inhibitory drugs include, but are notlimited to:

-   2-[1(-3-ethoxy-4-methoxyphenyl)-2-methyl-sulfonylethyl]isoindolin-1-one;-   2-[1-(3-ethoxy-4-methoxyphenyl)-2-(N,N-diethyl-aminosulfonyl)ethyl]isoindolin-1-one;-   2-[1-(3-ethoxy-4-methoxyphenyl)-2-methyl-sulfonylethyl]isoindoline-1,3-dione;-   2-[1-(3-ethoxy-4-methoxyphenyl)-2-methyl-sulfonylethyl]-5-nitro-isoindoline-1,3-dione;-   2-[1-(3-ethoxy-4-methoxyphenyl)-2-methyl-sulfonylethyl]-4-nitroisoindoline-1,3-dione;-   2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-aminoisoindoline-1,3-dione;-   2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-5-methylisoindoline-1,3-dione;-   2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-5-acetamidoisoindoline-1,3-dione;-   2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-dimethylaminoisondoline-1,3-dione;-   2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-5-dimethylaminoisoindoline-1,3-dione;-   2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]benzo[e]isoindoline-1,3-dione;-   2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-methoxyisoindoline-1,3-dione;-   1-(3-cyclopentyloxy-4-methoxyphenyl)-2-methylsulfonylethyl-amine;-   2-[1-(3-cyclopentyloxy-4-methoxyphenyl)-2-methylsulfonylethyl]isoindoline-1,3-dione;    and-   2-[1-(3-cyclopentyloxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-dimethylaminoisoindoline-1,3-dione.

Additional selective cytokine inhibitory drugs include theenantiomerically pure compounds disclosed in U.S. provisional patentapplication Nos. 60/366,515 and 60/366,516 to G. Muller et al., both ofwhich were filed Mar. 20, 2002; U.S. provisional patent application Nos.60/438,450 and 60/438,448 to G. Muller et al., both of which were filedon Jan. 7, 2003; and U.S. provisional patent application No. 60/452,460to G. Muller et al. filed on Mar. 5, 2003, all of which are incorporatedherein by reference. Specific compounds include an enantiomer of2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dioneand an enantiomer of3-(3,4-dimethoxy-phenyl)-3-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionamide.

Specific selective cytokine inhibitory drugs used in the invention are3-(3,4-dimethoxy-phenyl)-3-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionamideand cyclopropanecarboxylic acid{2-[1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide,which are available from Celgene Corp., Warren, N.J.3-(3,4-dimethoxy-phenyl)-3-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionamidehas the following chemical structure:

Cyclopropanecarboxylic acid{2-[1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amidehas the following chemical structure:

Compounds of the invention can either be commercially purchased orprepared according to the methods described in the patents or patentpublications disclosed herein. Further, optically pure compounds can beasymmetrically synthesized or resolved using known resolving agents orchiral columns as well as other standard synthetic organic chemistrytechniques.

As used herein and unless otherwise indicated, the term“pharmaceutically acceptable salt” encompasses non-toxic acid and baseaddition salts of the compound to which the term refers. Acceptablenon-toxic acid addition salts include those derived from organic andinorganic acids or bases know in the art, which include, for example,hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid,methanesulphonic acid, acetic acid, tartaric acid, lactic acid, succinicacid, citric acid, malic acid, maleic acid, sorbic acid, aconitic acid,salicylic acid, phthalic acid, embolic acid, enanthic acid, and thelike.

Compounds that are acidic in nature are capable of forming salts withvarious pharmaceutically acceptable bases. The bases that can be used toprepare pharmaceutically acceptable base addition salts of such acidiccompounds are those that form non-toxic base addition salts, i.e., saltscontaining pharmacologically acceptable cations such as, but not limitedto, alkali metal or alkaline earth metal salts and the calcium,magnesium, sodium or potassium salts in particular. Suitable organicbases include, but are not limited to, N,N-dibenzylethylenediamine,chloroprocaine, choline, diethanolamine, ethylenediamine, meglumaine(N-methylglucamine), lysine, and procaine.

As used herein and unless otherwise indicated, the term “prodrug” meansa derivative of a compound that can hydrolyze, oxidize, or otherwisereact under biological conditions (in vitro or in vivo) to provide thecompound. Examples of prodrugs include, but are not limited to,derivatives of selective cytokine inhibitory drugs of the invention thatcomprise biohydrolyzable moieties such as biohydrolyzable amides,biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzablecarbonates, biohydrolyzable ureides, and biohydrolyzable phosphateanalogues. Other examples of prodrugs include derivatives of selectivecytokine inhibitory drugs of the invention that comprise —NO, —NO₂,—ONO, or —ONO₂ moieties. Prodrugs can typically be prepared usingwell-known methods, such as those described in 1 Burger's MedicinalChemistry and Drug Discovery, 172-178, 949-982 (Manfred E. Wolff ed.,5th ed. 1995), and Design of Prodrugs (H. Bundgaard ed., Elselvier, NewYork 1985).

As used herein and unless otherwise indicated, the terms“biohydrolyzable amide,” “biohydrolyzable ester,” “biohydrolyzablecarbamate,” “biohydrolyzable carbonate,” “biohydrolyzable ureide,”“biohydrolyzable phosphate” mean an amide, ester, carbamate, carbonate,ureide, or phosphate, respectively, of a compound that either: 1) doesnot interfere with the biological activity of the compound but canconfer upon that compound advantageous properties in vivo, such asuptake, duration of action, or onset of action; or 2) is biologicallyinactive but is converted in vivo to the biologically active compound.Examples of biohydrolyzable esters include, but are not limited to,lower alkyl esters, lower acyloxyalkyl esters (such as acetoxylmethyl,acetoxyethyl, aminocarbonyloxymethyl, pivaloyloxymethyl, andpivaloyloxyethyl esters), lactonyl esters (such as phthalidyl andthiophthalidyl esters), lower alkoxyacyloxyalkyl esters (such asmethoxycarbonyl-oxymethyl, ethoxycarbonyloxyethyl andisopropoxycarbonyloxyethyl esters), alkoxyalkyl esters, choline esters,and acylamino alkyl esters (such as acetamidomethyl esters). Examples ofbiohydrolyzable amides include, but are not limited to, lower alkylamides, α-amino acid amides, alkoxyacyl amides, andalkylaminoalkylcarbonyl amides. Examples of biohydrolyzable carbamatesinclude, but are not limited to, lower alkylamines, substitutedethylenediamines, amino acids, hydroxyalkylamines, heterocyclic andheteroaromatic amines, and polyether amines.

Various selective cytokine inhibitory drugs of the invention contain oneor more chiral centers, and can exist as racemic mixtures of enantiomersor mixtures of diastereomers. This invention encompasses the use ofstereomerically pure forms of such compounds, as well as the use ofmixtures of those forms. For example, mixtures comprising equal orunequal amounts of the enantiomers of a particular selective cytokineinhibitory drugs of the invention may be used in methods andcompositions of the invention. These isomers may be asymmetricallysynthesized or resolved using standard techniques such as chiral columnsor chiral resolving agents. See, e.g. Jacques, J., et al., Enantiomers,Racemates and Resolutions (Wiley-Interscience, New York, 1981); Wilen,S. H., et al., Tetrahedron 33:2725 (1977); Eliel, E. L., Stereochemistryof Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, S. H., Tables ofResolving Agents and Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ.of Notre Dame Press, Notre Dame, Ind., 1972).

As used herein and unless otherwise indicated, the term “stereomericallypure” means a composition that comprises one stereoisomer of a compoundand is substantially free of other stereoisomers of that compound. Forexample, a stereomerically pure composition of a compound having onechiral center will be substantially free of the opposite enantiomer ofthe compound. A stereomerically pure composition of a compound havingtwo chiral centers will be substantially free of other diastereomers ofthe compound. A typical stereomerically pure compound comprises greaterthan about 80% by weight of one stereoisomer of the compound and lessthan about 20% by weight of other stereoisomers of the compound, morepreferably greater than about 90% by weight of one stereoisomer of thecompound and less than about 10% by weight of the other stereoisomers ofthe compound, even more preferably greater than about 95% by weight ofone stereoisomer of the compound and less than about 5% by weight of theother stereoisomers of the compound, and most preferably greater thanabout 97% by weight of one stereoisomer of the compound and less thanabout 3% by weight of the other stereoisomers of the compound. As usedherein and unless otherwise indicated, the term “stereomericallyenriched” means a composition that comprises greater than about 60% byweight of one stereoisomer of a compound, preferably greater than about70% by weight, more preferably greater than about 80% by weight of onestereoisomer of a compound. As used herein and unless otherwiseindicated, the term “enantiomerically pure” means a stereomerically purecomposition of a compound having one chiral center. Similarly, the term“stereomerically enriched” means a stereomerically enriched compositionof a compound having one chiral center.

It should be noted that if there is a discrepancy between a depictedstructure and a name given that structure, the depicted structure is tobe accorded more weight. In addition, if the stereochemistry of astructure or a portion of a structure is not indicated with, forexample, bold or dashed lines, the structure or portion of the structureis to be interpreted as encompassing all stereoisomers of it.

4.2 Second Active Agents

Selective cytokine inhibitory drugs can be combined with otherpharmacologically active compounds (“second active agents”) in methodsand compositions of the invention. It is believed that certaincombinations work synergistically in the treatment of particular typesof cancer and certain diseases and conditions associated with, orcharacterized by, undesired angiogenesis. Selective cytokine inhibitorydrugs can also work to alleviate adverse effects associated with certainsecond active agents, and some second active agents can be used toalleviate adverse effects associated with selective cytokine inhibitorydrugs.

One or more second active ingredients or agents can be used in themethods and compositions of the invention together with a selectivecytokine inhibitory drug. Second active agents can be large molecules(e.g., proteins) or small molecules (e.g., synthetic inorganic,organometallic, or organic molecules).

Examples of large molecule active agents include, but are not limitedto, hematopoietic growth factors, cytokines, and monoclonal andpolyclonal antibodies. Typical large molecule active agents arebiological molecules, such as naturally occurring or artificially madeproteins. Proteins that are particularly useful in this inventioninclude proteins that stimulate the survival and/or proliferation ofhematopoietic precursor cells and immunologically active poietic cellsin vitro or in vivo. Others stimulate the division and differentiationof committed erythroid progenitors in cells in vitro or in vivo.Particular proteins include, but are not limited to: interleukins, suchas IL-2 (including recombinant IL-II (“rIL2”) and canarypox IL-2),IL-10, IL-12, and IL-18; interferons, such as interferon alfa-2a,interferon alfa-2b, interferon alfa-n1, interferon alfa-n3, interferonbeta-I a, and interferon gamma-I b; GM-CF and GM-CSF; and EPO.

Particular proteins that can be used in the methods and compositions ofthe invention include, but are not limited to: filgrastim, which is soldin the United States under the trade name Neupogen® (Amgen, ThousandOaks, Calif.); sargramostim, which is sold in the United States underthe trade name Leuline® (Immunex, Seattle, Wash.); and recombinant EPO,which is sold in the United States under the trade name Epogen® (Amgen,Thousand Oaks, Calif.).

Recombinant and mutated forms of GM-CSF can be prepared as described inU.S. Pat. Nos. 5,391,485; 5,393,870; and 5,229,496; all of which areincorporated herein by reference. Recombinant and mutated forms of G-CSFcan be prepared as described in U.S. Pat. Nos. 4,810,643; 4,999,291;5,528,823; and 5,580,755; all of which are incorporated herein byreference.

This invention encompasses the use of native, naturally occurring, andrecombinant proteins. The invention further encompasses mutants andderivatives (e.g., modified forms) of naturally occurring proteins thatexhibit, in vivo, at least some of the pharmacological activity of theproteins upon which they are based. Examples of mutants include, but arenot limited to, proteins that have one or more amino acid residues thatdiffer from the corresponding residues in the naturally occurring formsof the proteins. Also encompassed by the term “mutants” are proteinsthat lack carbohydrate moieties normally present in their naturallyoccurring forms (e.g., nonglycosylated forms). Examples of derivativesinclude, but are not limited to, pegylated derivatives and fusionproteins, such as proteins formed by fusing IgG1 or IgG3 to the proteinor active portion of the protein of interest. See, e.g., Penichet, M. L.and Morrison, S. L., J. Immunol. Methods 248:91-101 (2001).

Antibodies that can be used in combination with compounds of theinvention include monoclonal and polyclonal antibodies. Examples ofantibodies include, but are not limited to, trastuzumab (Herceptin®),rituximab (Rituxan®), bevacizumab (Avastin™), pertuzumab (Omnitarg™),tositumomab (Bexxar®), edrecolomab (Panorex®), and G250. Compounds ofthe invention can also be combined with, or used in combination with,anti-TNF-α antibodies.

Large molecule active agents may be administered in the form ofanti-cancer vaccines. For example, vaccines that secrete, or cause thesecretion of, cytokines such as IL-2, G-CSF, and GM-CSF can be used inthe methods, pharmaceutical compositions, and kits of the invention.See, e.g., Emens, L. A., et al., Curr. Opinion Mol. Ther. 3(1):77-84(2001).

In one embodiment of the invention, the large molecule active agentreduces, eliminates, or prevents an adverse effect associated with theadministration of a selective cytokine inhibitory drug. Depending on theparticular selective cytokine inhibitory drug and the disease ordisorder begin treated, adverse effects can include, but are not limitedto, drowsiness and somnolence, dizziness and orthostatic hypotension,neutropenia, infections that result from neutropenia, increasedHIV-viral load, bradycardia, Stevens-Johnson Syndrome and toxicepidermal necrolysis, and seizures (e.g., grand mal convulsions). Aspecific adverse effect is neutropenia.

Second active agents that are small molecules can also be used toalleviate adverse effects associated with the administration of aselective cytokine inhibitory drug. However, like some large molecules,many are believed to be capable of providing a synergistic effect whenadministered with (e.g., before, after or simultaneously) a selectivecytokine inhibitory drug. Examples of small molecule second activeagents include, but are not limited to, anti-cancer agents, antibiotics,immunosuppressive agents, and steroids.

Examples of anti-cancer agents include, but are not limited to:acivicin; aclarubicin; acodazole hydrochloride; acronine; adozelesin;aldesleukin; altretamine; ambomycin; ametantrone acetate; amsacrine;anastrozole; anthramycin; asparaginase; asperlin; azacitidine; azetepa;azotomycin; batimastat; benzodepa; bicalutamide; bisantrenehydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate;brequinar sodium; bropirimine; busulfan; cactinomycin; calusterone;caracemide; carbetimer, carboplatin; carmustine; carubicinhydrochloride; carzelesin; cedefingol; celecoxib (COX-2 inhibitor);chlorambucil; cirolemycin; cisplatin; cladribine; crisnatol mesylate;cyclophosphamide; cytarabine; dacarbazine; dactinomycin; daunorubicinhydrochloride; decitabine; dexormaplatin; dezaguanine; dezaguaninemesylate; diaziquone; docetaxel; doxorubicin; doxorubicin hydrochloride;droloxifene; droloxifene citrate; dromostanolone propionate; duazomycin;edatrexate; eflornithine hydrochloride; elsamitrucin; enloplatin;enpromate; epipropidine; epirubicin hydrochloride; erbulozole;esorubicin hydrochloride; estramustine; estramustine phosphate sodium;etanidazole; etoposide; etoposide phosphate; etoprine; fadrozolehydrochloride; fazarabine; fenretinide; floxuridine; fludarabinephosphate; fluorouracil; fluorocitabine; fosquidone; fostriecin sodium;gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicinhydrochloride; ifosfamide; ilmofosine; iproplatin; irinotecan;irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolideacetate; liarozole hydrochloride; lometrexol sodium; lomustine;losoxantrone hydrochloride; masoprocol; maytansine; mechlorethaminehydrochloride; megestrol acetate; melengestrol acetate; melphalan;menogaril; mercaptopurine; methotrexate; methotrexate sodium; metoprine;meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin; mitomalcin;mitomycin; mitosper, mitotane; mitoxantrone hydrochloride; mycophenolicacid; nocodazole; nogalamycin; ormaplatin; oxisuran; paclitaxel;pegaspargase; peliomycin; pentamustine; peplomycin sulfate;perfosfamide; pipobroman; piposulfan; piroxantrone hydrochloride;plicamycin; plomestane; porfimer sodium; porfiromycin; prednimustine;procarbazine hydrochloride; puromycin; puromycin hydrochloride;pyrazofurin; riboprine; safingol; safingol hydrochloride; semustine;simtrazene; sparfosate sodium; sparsomycin; spirogermaniumhydrochloride; spiromustine; spiroplatin; streptonigrin; streptozocin;sulofenur; talisomycin; tecogalan sodium; taxotere; tegafur;teloxantrone hydrochloride; temoporfin; teniposide; teroxirone;testolactone; thiamiprine; thioguanine; thiotepa; tiazofurin;tirapazamine; toremifene citrate; trestolone acetate; triciribinephosphate; trimetrexate; trimetrexate glucuronate; triptorelin;tubulozole hydrochloride; uracil mustard; uredepa; vapreotide;verteporfin; vinblastine sulfate; vincristine sulfate; vindesine;vindesine sulfate; vinepidine sulfate; vinglycinate sulfate;vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate;vinzolidine sulfate; vorozole; zeniplatin; zinostatin; and zorubicinhydrochloride.

Other anti-cancer drugs include, but are not limited to: 20-epi-1,25dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin;acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists;altretamine; ambamustine; amidox; amifostine; aminolevulinic acid;amrubicin; amsacrine; anagrelide; anastrozole; andrographolide;angiogenesis inhibitors; antagonist D; antagonist G; antarelix;anti-dorsalizing morphogenetic protein-1; antiandrogen, prostaticcarcinoma; antiestrogen; antineoplaston; antisense oligonucleotides;aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators;apurinic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine;atamestane; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3;azasetron; azatoxin; azatyrosine; baccatin III derivatives; balanol;batimastat; BCR/ABL antagonists; benzochlorins; benzoylstaurosporine;beta lactam derivatives; beta-alethine; betaclamycin B; betulinic acid;bFGF inhibitor; bicalutamide; bisantrene; bisaziridinylspermine;bisnafide; bistratene A; bizelesin; breflate; bropirimine; budotitane;buthionine sulfoximine; calcipotriol; calphostin C; camptothecinderivatives; capecitabine; carboxamide-amino-triazole;carboxyamidotriazole; CaRest M3; CARN 700; cartilage derived inhibitor;carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropinB; cetrorelix; chlorins; chloroquinoxaline sulfonamide; cicaprost;cis-porphyrin; cladribine; clomifene analogues; clotrimazole;collismycin A; collismycin B; combretastatin A4; combretastatinanalogue; conagenin; crambescidin 816; crisnatol; cryptophycin 8;cryptophycin A derivatives; curacin A; cyclopentanthraquinones;cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor;cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin;dexamethasone; dexifosfamide; dexrazoxane; dexverapamil; diaziquone;didemnin B; didox; diethylnorspermine; dihydro-5-azacytidine;dihydrotaxol, 9-; dioxamycin; diphenyl spiromustine; docetaxel;docosanol; dolasetron; doxifluridine; doxorubicin; droloxifene;dronabinol; duocarmycin SA; ebselen; ecomustine; edelfosine;edrecolomab; eflornithine; elemene; emitefur; epirubicin; epristeride;estramustine analogue; estrogen agonists; estrogen antagonists;etanidazole; etoposide phosphate; exemestane; fadrozole; fazarabine;fenretinide; filgrastim; finasteride; flavopiridol; flezelastine;fluasterone; fludarabine; fluorodaunorunicin hydrochloride; forfenimex;formestane; fostriecin; fotemustine; gadolinium texaphyrin; galliumnitrate; galocitabine; ganirelix; gelatinase inhibitors; gemcitabine;glutathione inhibitors; hepsulfam; heregulin; hexamethylenebisacetamide; hypericin; ibandronic acid; idarubicin; idoxifene;idramantone; ilmofosine; ilomastat; imatinib (e.g., Gleevec®),imiquimod; immunostimulant peptides; insulin-like growth factor-1receptor inhibitor; interferon agonists; interferons; interleukins;iobenguane; iododoxorubicin; ipomeanol, 4-; iroplact; irsogladine;isobengazole; isohomohalicondrin B; itasetron; jasplakinolide;kahalalide F; lamellarin-N triacetate; lanreotide; leinamycin;lenograstim; lentinan sulfate; leptolstatin; letrozole; leukemiainhibiting factor; leukocyte alpha interferon;leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole;linear polyamine analogue; lipophilic disaccharide peptide; lipophilicplatinum compounds; lissoclinamide 7; lobaplatin; lombricine;lometrexol; lonidamine; losoxantrone; loxoribine; lurtotecan; lutetiumtexaphyrin; lysofylline; lytic peptides; maitansine; mannostatin A;marimastat; masoprocol; maspin; matrilysin inhibitors; matrixmetalloproteinase inhibitors; menogaril; merbarone; meterelin;methioninase; metoclopramide; MIF inhibitor, mifepristone; miltefosine;mirimostim; mitoguazone; mitolactol; mitomycin analogues; mitonafide;mitotoxin fibroblast growth factor-saporin; mitoxantrone; mofarotene;molgramostim; Erbitux, human chorionic gonadotrophin; monophosphoryllipid A+myobacterium cell wall sk; mopidamol; mustard anticancer agent;mycaperoxide B; mycobacterial cell wall extract; myriaporone;N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip;naloxone+pentazocine; napavin; naphterpin; nartograstim; nedaplatin;nemorubicin; neridronic acid; nilutamide; nisamycin; nitric oxidemodulators; nitroxide antioxidant; nitrullyn; oblimersen (Genasense®);O⁶-benzylguanine; octreotide; okicenone; oligonucleotides; onapristone;ondansetron; ondansetron; oracin; oral cytokine inducer, ormaplatin;osaterone; oxaliplatin; oxaunomycin; paclitaxel; paclitaxel analogues;paclitaxel derivatives; palauamine; palmitoylrhizoxin; pamidronic acid;panaxytriol; panomifene; parabactin; pazelliptine; pegaspargase;peldesine; pentosan polysulfate sodium; pentostatin; pentrozole;perflubron; perfosfamide; perillyl alcohol; phenazinomycin;phenylacetate; phosphatase inhibitors; picibanil; pilocarpinehydrochloride; pirarubicin; piritrexim; placetin A; placetin B;plasminogen activator inhibitor, platinum complex; platinum compounds;platinum-triamine complex; porfimer sodium; porfiromycin; prednisone;propyl bis-acridone; prostaglandin J2; proteasome inhibitors; proteinA-based immune modulator; protein kinase C inhibitor; protein kinase Cinhibitors, microalgal; protein tyrosine phosphatase inhibitors; purinenucleoside phosphorylase inhibitors; purpurins; pyrazoloacridine;pyridoxylated hemoglobin polyoxyethylene conjugate; raf antagonists;raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors;ras inhibitors; ras-GAP inhibitor; retelliptine demethylated; rhenium Re186 etidronate; rhizoxin; ribozymes; RII retinamide; rohitukine;romurtide; roquinimex; rubiginone B1; ruboxyl; safingol; saintopin;SarCNU; sarcophytol A; sargramostim; Sdi 1 mimetics; semustine;senescence derived inhibitor 1; sense oligonucleotides; signaltransduction inhibitors; sizofuran; sobuzoxane; sodium borocaptate;sodium phenylacetate; solverol; somatomedin binding protein; sonermin;sparfosic acid; spicamycin D; spiromustine; splenopentin; spongistatin1; squalamine; stipiamide; stromelysin inhibitors; sulfinosine;superactive vasoactive intestinal peptide antagonist; suradista;suramin; swainsonine; tallimustine; tamoxifen methiodide; tauromustine;tazarotene; tecogalan sodium; tegafur; tellurapyrylium; telomeraseinhibitors; temoporfin; teniposide; tetrachlorodecaoxide; tetrazomine;thaliblastine; thiocoraline; thrombopoietin; thrombopoietin mimetic;thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroidstimulating hormone; tin ethyl etiopurpurin; tirapazamine; titanocenebichloride; topsentin; toremifene; translation inhibitors; tretinoin;triacetyluridine; triciribine; trimetrexate; triptorelin; tropisetron;turosteride; tyrosine kinase inhibitors; tyrphostins; UBC inhibitors;ubenimex; urogenital sinus-derived growth inhibitory factor; urokinasereceptor antagonists; vapreotide; variolin B; velaresol; veramine;verdins; verteporfin; vinorelbine; vinxaltine; vitaxin; vorozole;zanoterone; zeniplatin; zilascorb; and zinostatin stimalamer.

Specific second active agents include, but are not limited to,oblimersen (Genasense®), remicade, docetaxel, celecoxib, melphalan,dexamethasone (Decadron®), steroids, gemcitabine, cisplatinum,temozolomide, etoposide, cyclophosphamide, temodar, carboplatin,procarbazine, gliadel, tamoxifen, topotecan, methotrexate, Arisa®,taxol, taxotere, fluorouracil, leucovorin, irinotecan, xeloda, CPT-11,interferon alpha, pegylated interferon alpha (e.g., PEG INTRON-A),capecitabine, cisplatin, thiotepa, fludarabine, carboplatin, liposomaldaunorubicin, cytarabine, doxetaxol, pacilitaxel, vinblastine, IL-2,GM-CSF, dacarbazine, vinorelbine, zoledronic acid, palmitronate, biaxin,busulphan, prednisone, bisphosphonate, arsenic trioxide, vincristine,doxorubicin (Doxil®), paclitaxel, ganciclovir, adriamycin, estrainustinesodium phosphate (Emcyt®), sulindac, and etoposide.

4.3 Methods of Treatments and Prevention

Methods of this invention encompass methods of treating, preventingand/or managing various types of cancer and diseases and disordersassociated with, or characterized by, undesired angiogenesis. As usedherein, unless otherwise specified, the term “treating” refers to theadministration of a compound of the invention or other additional activeagent after the onset of symptoms of the particular disease or disorder.As used herein, unless otherwise specified, the term “preventing” refersto the administration prior to the onset of symptoms, particularly topatients at risk of cancer, and other diseases and disorders associatedwith, or characterized by, undesired angiogenesis. The term “prevention”includes the inhibition of a symptom of the particular disease ordisorder. Patients with familial history of cancer and diseases anddisorders associated with, or characterized by, undesired angiogenesisare preferred candidates for preventive regimens. As used herein andunless otherwise indicated, the term “managing” encompasses preventingthe recurrence of the particular disease or disorder in a patient whohad suffered from it, and/or lengthening the time a patient who hadsuffered from the disease or disorder remains in remission.

As used herein, the term “cancer” includes, but is not limited to, solidtumors and blood born tumors. The term “cancer” refers to disease ofskin tissues, organs, blood, and vessels, including, but not limited to,cancers of the bladder, bone or blood, brain, breast, cervix, chest,colon, endrometrium, esophagus, eye, head, kidney, liver, lymph nodes,lung, mouth, neck, ovaries, pancreas, prostate, rectum, stomach, testis,throat, and uterus. Specific cancers include, but are not limited to,advanced malignancy, amyloidosis, neuroblastoma, meningioma,hemangiopericytoma, multiple brain metastase, glioblastoma multiforms,glioblastoma, brain stem glioma, poor prognosis malignant brain tumor,malignant glioma, recurrent malignant glioma, anaplastic astrocytoma,anaplastic oligodendroglioma, neuroendocrine tumor, rectaladenocarcinoma, Dukes C & D colorectal cancer, unresectable colorectalcarcinoma, metastatic hepatocellular carcinoma, Kaposi's sarcoma,karotype acute myeloblastic leukemia, Hodgkin's lymphoma, non-Hodgkin'slymphoma, cutaneous T-Cell lymphoma, cutaneous B-Cell lymphoma, diffuselarge B-Cell lymphoma, low grade follicular lymphoma, malignantmelanoma, malignant mesothelioma, malignant pleural effusionmesothelioma syndrome, peritoneal carcinoma, papillary serous carcinoma,gynecologic sarcoma, soft tissue sarcoma, scelroderma, cutaneousvasculitis, Langerhans cell histiocytosis, leiomyosarcoma,fibrodysplasia ossificans progressive, hormone refractory prostatecancer, resected high-risk soft tissue sarcoma, unrescectablehepatocellular carcinoma, Waldenstrom's macroglobulinemia, smolderingmyeloma, indolent myeloma, fallopian tube cancer, androgen independentprostate cancer, androgen dependent stage IV non-metastatic prostatecancer, hormone-insensitive prostate cancer, chemotherapy-insensitiveprostate cancer, papillary thyroid carcinoma, follicular thyroidcarcinoma, medullary thyroid carcinoma, and leiomyoma. In a specificembodiment, the cancer is metastatic. In another embodiment, the canceris refractory or resistance to chemotherapy or radiation; in particular,refractory to thalidomide.

As used herein to refer to diseases and conditions other than cancer,the terms “diseases or disorders associated with, or characterized by,undesired angiogenesis,” “diseases or disorders associated withundesired angiogenesis,” and “diseases or disorders characterized byundesired angiogenesis” refer to diseases, disorders and conditions thatare caused, mediated or attended by undesired, unwanted or uncontrolledangiogenesis, including, but not limited to, inflammatory diseases,autoimmune diseases, genetic diseases, allergic diseases, bacterialdiseases, ocular neovascular diseases, choroidal neovascular diseases,and retina neovascular diseases.

Examples of such diseases or disorders associated with undesiredangiogenesis include, but are not limited to, diabetic retinopathy,retinopathy of prematurity, corneal graft rejection, neovascularglaucoma, retrolental fibroplasia, proliferative vitreoretinopathy,trachoma, myopia, optic pits, epidemnic keratoconjunctivitis, atopickeratitis, superior limbic keratitis, pterygium keratitis sicca,sjogrens, acne rosacea, phylectenulosis, syphilis, lipid degeneration,bacterial ulcer, fungal ulcer, Herpes simplex infection, Herpes zosterinfection, protozoan infection, Kaposi sarcoma, Mooren ulcer, Terrien'smarginal degeneration, mariginal keratolysis, rheumatoid arthritis,systemic lupus, polyarteritis, trauma, Wegeners sarcoidosis, Scleritis,Steven's Johnson disease, periphigoid radial keratotomy, sickle cellanemia, sarcoid, pseudoxanthoma elasticum, Pagets disease, veinocclusion, artery occlusion, carotid obstructive disease, chronicuveitis, chronic vitritis, Lyme's disease, Eales disease, Bechetsdisease, retinitis, choroiditis, presumed ocular histoplasmosis, Bestsdisease, Stargarts disease, pars planitis, chronic retinal detachment,hyperviscosity syndromes, toxoplasmosis, rubeosis, sarcodisis,sclerosis, soriatis, psoriasis, primary sclerosing cholangitis,proctitis, primary biliary srosis, idiopathic pulmonary fibrosis, andalcoholic hepatitis.

In specific embodiments of the invention, diseases or disordersassociated with undesired angiogenesis do not include congestive heartfailure, cardiomyopathy, pulmonary edema, endotoxin-mediated septicshock, acute viral myocarditis, cardiac allograft rejection, myocardialinfarction, HIV, hepatitis, adult respiratory distress syndrome,bone-resorption disease, chronic obstructive pulmonary diseases, chronicpulmonary inflammatory disease, dermatitis, cystic fibrosis, septicshock, sepsis, endotoxic shock, hemodynamic shock, sepsis syndrome, postischemic reperfusion injury, meningitis, psoriasis, fibrotic disease,cachexia, graft rejection, rheumatoid spondylitis, osteoporosis, Crohn'sdisease, ulcerative colitis, inflammatory-bowel disease, multiplesclerosis, systemic lupus erythrematosus, erythema nodosum leprosum inleprosy, radiation damage, asthma, hyperoxic alveolar injury, malaria,mycobacterial infection, and opportunistic infections resulting fromHIV.

This invention encompasses methods of treating patients who have beenpreviously treated for cancer or diseases or disorders associated with,or characterized by, undesired angiogenesis, but are non-responsive tostandard therapies, as well as those who have not previously beentreated. The invention also encompasses methods of treating patientsregardless of patient's age, although some diseases or disorders aremore common in certain age groups. The invention further encompassesmethods of treating patients who have undergone surgery in an attempt totreat the disease or condition at issue, as well as those who have not.Because patients with cancer and diseases and disorders characterized byundesired angiogenesis have heterogenous clinical manifestations andvarying clinical outcomes, the treatment given to a patient may vary,depending on his/her prognosis. The skilled clinician will be able toreadily determine without undue experimentation specific secondaryagents, types of surgery, and types of non-drug based standard therapythat can be effectively used to treat an individual patient with cancerand other diseases or disorders.

Methods encompassed by this invention comprise administering one or moreselective cytokine inhibitory drug of the invention, or apharmaceutically acceptable salt, solvate, hydrate, stereoisomer,clathrate, or prodrug thereof, to a patient (e.g., a human) suffering,or likely to suffer, from cancer or a disease or disorder mediated byundesired angiogenesis.

In one embodiment of the invention, the recommended daily dose range ofa selective cytokine inhibitory drug for the conditions described hereinlie within the range of from about 1 mg to about 10,000 mg per day,given as a single once-a-day dose, or preferably in divided dosesthroughout a day. More specifically, the daily dose is administeredtwice daily in equally divided doses. Specifically, a daily dose rangeshould be from about 1 mg to about 5,000 mg per day, more specifically,between about 10 mg and about 2,500 mg per day, between about 100 mg andabout 800 mg per day, between about 100 mg and about 1,200 mg per day,or between about 25 mg and about 2,500 mg per day. In managing thepatient, the therapy should be initiated at a lower dose, perhaps about1 mg to about 2,500 mg, and increased if necessary up to about 200 mg toabout 5,000 mg per day as either a single dose or divided doses,depending on the patient's global response. In a particular embodiment,3-(3,4-dimethoxy-phenyl)-3-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionamidecan be preferably administered in an amount of about 400, 800, 1,200,2,500, 5,000 or 10,000 mg a day as two divided doses.

In a specific embodiment,3-(3,4-dimethoxy-phenyl)-3-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionamidemay be administered in an amount of about 400, 800, or 1,200 mg per dayto patients with relapsed multiple myeloma. In a particular embodiment,3-(3,4-dimethoxy-phenyl)-3-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionamidemay be administered initially in an amount of 100 mg/day and the dosecan be escalated every week to 200, 400, 800, 1,200, and 2,500 mg/day.In a specific embodiment, the compound can be administered in an amountof up to about 5,000 mg/day to patients with solid tumor. In aparticular embodiment, the compound can be administered in an amount ofup to about 10,000 mg/day to patients with glioma.

In a specific embodiment,3-(3,4-dimethoxy-phenyl)-3-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionamidemay be administered to patients with Crohn's disease initially in anamount of 400 mg and can be escalated to 800-mg and 1200 mg daily.

4.3.1 Combination Therapy with a Second Active Agent

Specific methods of the invention comprise administering a selectivecytokine inhibitory drug of the invention, or a pharmaceuticallyacceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrugthereof, in combination with one or more second active agents, and/or incombination with radiation therapy, blood transfusions, or surgery.Examples of selective cytokine inhibitory drugs of the invention aredisclosed herein (see, e.g., section 4.1). Examples of second activeagents are also disclosed herein (see, e.g., section 4.2).

Administration of the selective cytokine inhibitory drugs and the secondactive agents to a patient can occur simultaneously or sequentially bythe same or different routes of administration. The suitability of aparticular route of administration employed for a particular activeagent-will depend on the active agent itself (e.g. whether it can beadministered orally without decomposing prior to entering the bloodstream) and the disease being treated. A preferred route ofadministration for a selective cytokine inhibitory drug of the inventionis oral or ophthalmic. Preferred routes of administration for the secondactive agents or ingredients of the invention are known to those ofordinary skill in the art. See, e.g., Physicians' Desk Reference,1755-1760 (56^(th) ed., 2002).

In one embodiment of the invention, the second active agent isadministered intravenously or subcutaneously and once or twice daily inan amount of from about 1 to about 1000 mg, from about 5 to about 500mg, from about 10 to about 350 mg, or from about 50 to about 200 mg. Thespecific amount of the second active agent will depend on the specificagent used, the type of disease being treated or managed, the severityand stage of disease, and the amount(s) of selective cytokine inhibitorydrugs of the invention and any optional additional active agentsconcurrently administered to the patient. In a particular embodiment,the second active agent is oblimersen (Genasense®), GM-CSF, G-CSF, EPO,taxotere, irinotecan, dacarbazine, transretinoic acid, topotecan,pentoxifylline, ciprofloxacin, dexamethasone, vincristine, doxorubicin,cox-2 inhibitors, IL2, IL8, IL18, IFN, Ara-C, vinorelbine, or acombination thereof.

In a particular embodiment, GM-CSF, G-CSF or EPO is administeredsubcutaneously during about five days in a four or six week cycle in anamount of from about 1 to about 750 mg/m² day, preferably in an amountof from about 25 to about 500 mg/m²/day, more preferably in an amount offrom about 50 to about 250 mg/m²/day, and most preferably in an amountof from about 50 to about 200 mg/m²/day. In a certain embodiment, GM-CSFmay be administered in an amount of from about 60 to about 500 mcg/m²intravenously over 2 hours, or from about 5 to about 12 mcg/m²/daysubcutaneously. In a specific embodiment, G-CSF may be administeredsubcutaneously in an amount of about 1 mcg/kg/day initially and can beadjusted depending on rise of total granulocyte counts. The maintenancedose of G-CSF may be administered in an amount of about 300 (in smallerpatients) or 480 mcg subcutaneously. In a certain embodiment, EPO may beadministered subcutaneously in an amount of 10,000 Unit 3 times perweek.

In another embodiment, 3-(3,4-dimethoxy-phenyl)-3-(1oxo-1,3-dihydro-isoindol-2-yl)-propionamide in an amount of about 25mg/d and dacarbazine in an amount of about from 800 to 1,200 mg/m²/d areadministered to patients with metastatic malignant melanoma. In aspecific embodiment,3-(3,4-dimethoxy-phenyl)-3-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionamideis administered in an amount of from about 200 to about 800 mg/d topatients with metastatic malignant melanoma whose disease has progressedon treatment with dacarbazine, IL-2 or IFN. In a specific embodiment,3-(3,4-dimethoxy-phenyl)-3-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionamideis administered to patients with relapsed or refractory multiple myelomain an amount of about 400 mg/d twice a day or about 800 mg/d four timesa day in a combination with dexamethasone.

In another embodiment, a selective cytokine inhibitory drug isadministered with melphalan and dexamethasone to patients withamyloidosis. In a specific embodiment, a selective cytokine inhibitorydrug of the invention and steroids can be administered to patients withamyloidosis.

In another embodiment, a selective cytokine inhibitory drug isadministered with gemcitabine and cisplatinum to patients with locallyadvanced or metastatic transitional cell bladder cancer.

In another embodiment, a selective cytokine inhibitory drug isadministered in combination with a second active ingredient as follows:temozolomide to pediatric patients with relapsed or progressive braintumors or recurrent neuroblastoma; celecoxib, etoposide andcyclophosphamide for relapsed or progressive CNS cancer; temodar topatients with recurrent or progressive meningioma, malignant meningioma,hemangiopericytoma, multiple brain metastases, relapased brain tumors,or newly diagnosed glioblastoma multiforms; irinotecan to patients withrecurrent glioblastoma; carboplatin to pediatric patients with brainstem glioma; procarbazine to pediatric patients with progressivemalignant gliomas; cyclophosphamide to patients with poor prognosismalignant brain tumors, newly diagnosed or recurrent glioblastomamultiforms; Gliadel® for high grade recurrent malignant gliomas;temozolomide and tamoxifen for anaplastic astrocytoma; or topotecan forgliomas, glioblastoma, anaplastic astrocytoma or anaplasticoligodendroglioma.

In another embodiment, a selective cytokine inhibitory drug isadministered with methotrexate and cyclophosphamide to patients withmetastatic breast cancer.

In another embodiment, a selective cytokine inhibitory drug isadministered with temozolomide to patients with neuroendocrine tumors.

In another embodiment, a selective cytokine inhibitory drug isadministered with gemcitabine to patients with recurrent or metastatichead or neck cancer. In another embodiment, a selective cytokineinhibitory drug is administered with gemcitabine to patients withpancreatic cancer.

In another embodiment, a selective cytokine inhibitory drug isadministered to patients with colon cancer in combination with Arisa®,taxol and/or taxotere.

In another embodiment, a selective cytokine inhibitory drug isadministered with capecitabine to patients with refractory colorectalcancer or patients who fail first line therapy or have poor performancein colon or rectal adenocarcinoma.

In another embodiment, a selective cytokine inhibitory drug isadministered in combination with fluorouracil, leucovorin, andirinotecan to patients with Dukes C & D colorectal cancer or to patientswho have been previously treated for metastatic colorectal cancer.

In another embodiment, a selective cytokine inhibitory drug isadministered to patients with refractory colorectal cancer incombination with capecitabine, xeloda, and/or CPT-11.

In another embodiment, a selective cytokine inhibitory drug of theinvention is administered with capecitabine and irinotecan to patientswith refractory colorectal cancer or to patients with unresectable ormetastatic colorectal carcinoma.

In another embodiment, a selective cytokine inhibitory drug isadministered alone or in combination with interferon alpha orcapecitabine to patients with unresectable or metastatic hepatocellularcarcinoma; or with cisplatin and thiotepa to patients with primary ormetastatic liver cancer.

In another embodiment, a selective cytokine inhibitory drug isadministered in combination with pegylated interferon alpha to patientswith Kaposi's sarcoma.

In another embodiment, a selective cytokine inhibitory drug isadministered in combination with fludarabine, carboplatin, and/ortopotecan to patients with refractory or relapsed or high-risk acutedmyelogenous leukemia.

In another embodiment, a selective cytokine inhibitory drug isadministered in combination with liposomal daunorubicin, topotecanand/or cytarabine to patients with unfavorable karotype acutemyeloblastic leukemia.

In another embodiment, a selective cytokine inhibitory drug isadministered in combination with gemcitabine and irinotecan to patientswith non-small cell lung cancer. In one embodiment, a selective cytokineinhibitory drug is administered in combination with carboplatin andirinotecan to patients with non-small cell lung cancer. In oneembodiment, a selective cytokine inhibitory drug is administered withdoxetaxol to patients with non-small cell lung cancer who have beenpreviously treated with carbo/VP 16 and radiotherapy.

In another embodiment, a selective cytokine inhibitory drug isadministered in combination with carboplatin and/or taxotere, or incombination with carboplatin, pacilitaxel and/or thoracic radiotherapyto patients with non-small cell lung cancer. In a specific embodiment, aselective cytokine inhibitory drug is administered in combination withtaxotere to patients with stage IIIB or IV non-small cell lung cancer.

In another embodiment, a selective cytokine inhibitory drug of theinvention is administered in combination with oblimersen (Genasense®) topatients with small cell lung cancer.

In another embodiment, a selective cytokine inhibitory drug isadministered alone or in combination with a second active ingredientsuch as vinblastine or fludarabine to patients with various types oflymphoma, including, but not limited to, Hodgkin's lymphoma,non-Hodgkin's lymphoma, cutaneous T-Cell lymphoma, cutaneous B-Celllymphoma, diffuse large B-Cell lymphoma or relapsed or refractory lowgrade follicular lymphoma.

In another embodiment, a selective cytokine inhibitory drug isadministered in combination with taxotere, IL-2, IFN; GM-CSF, and/ordacarbazine to patients with various types or stages of melanoma.

In another embodiment, a selective cytokine inhibitory drug isadministered alone or in combination with vinorelbine to patients withmalignant mesothelioma, or stage IIIB non-small cell lung cancer withpleural implants or malignant pleural effusion mesothelioma syndrome.

In another embodiment, a selective cytokine inhibitory drug isadministered to patients with various types or stages of multiplemyeloma in combination with dexamethasone, zoledronic acid,palmitronate, GM-CSF, biaxin, vinblastine, melphalan, busulphan,cyclophosphamide, IFN, palmidronate, prednisone, bisphosphonate,celecoxib, arsenic trioxide, PEG INTRON-A, vincristine, doxil, decadron,or a combination thereof.

In another embodiment, a selective cytokine inhibitory drug isadministered to patients with relapsed or refractory multiple myeloma incombination with doxorubicin (Doxil®), vincristine and/or dexamethasone(Decadron®).

In another embodiment, a selective cytokine inhibitory drug isadministered to patients with various types or stages of ovarian cancersuch as peritoneal carcinoma, papillary serous carcinoma, refractoryovarian cancer or recurrent ovarian cancer, in combination with taxol,carboplatin, doxorubicin, gemcitabine, cisplatin, xeloda, paclitaxel,dexamethasone, or a combination thereof.

In another embodiment, a selective cytokine inhibitory drug isadministered to patients with various types or stages of prostatecancer, in combination with xeloda, 5 FU/LV, gemcitabine, irinotecanplus gemcitabine, cyclophosphamide, vincristine, dexamethasone, GM-CSF,celecoxib, taxotere, ganciclovir, paclitaxel, adriamycin, docetaxel,estramustine, Emcyt, or a combination thereof.

In another embodiment, a selective cytokine inhibitory drug isadministered to patients with various types or stages of renal cellcancer, in combination with capecitabine, IFN, tamoxifen, IL-2, GM-CSF,Celebrex®, or a combination thereof.

In another embodiment, a selective cytokine inhibitory drug isadministered to patients with various types or stages of gynecologic,uterus or soft tissue sarcoma cancer in combination with IFN, a COX-2inhibitor such as Celebrex®, and/or sulindac.

In another embodiment, a selective cytokine inhibitory drug isadministered to patients with various types or stages of solid tumors incombination with celebrex, etoposide, cyclophosphamide, docetaxel,apecitabine, IFN, tamoxifen, IL-2, GM-CSF, or a combination thereof.

In another embodiment, a selective cytokine inhibitory drug isadministered to patients with scelroderma or cutaneous vasculitis incombination with celebrex, etoposide, cyclophosphamide, docetaxel,apecitabine, IFN, tamoxifen, IL-2, GM-CSF, or a combination thereof.

This invention also encompasses a method of increasing the dosage of ananti-cancer drug or agent that can be safely and effectivelyadministered to a patient, which comprises administering to a patient(e.g., a human) a selective cytokine inhibitory drug of the invention,or a pharmaceutically acceptable derivative, salt, solvate, clathrate,hydrate, or prodrug thereof. Patients that can benefit by this methodare those likely to suffer from an adverse effect associated withanti-cancer drugs for treating a specific cancer of the skin,subcutaneous tissue, lymph nodes, brain, lung, liver, bone, intestine,colon, heart, pancreas, adrenal, kidney, prostate, breast, colorectal,or combinations thereof. The administration of a selective cytokineinhibitory drug of the invention alleviates or reduces adverse effectswhich are of such severity that it would otherwise limit the amount ofanti-cancer drug.

In one embodiment, a selective cytokine inhibitory drug of the inventioncan be administered orally and daily in an amount of from about 1 toabout 5,000 mg, from about 10 to about 2,500 mg, from about 25 to about2,500 mg, from about 100 to about 1,200 mg, or from about 100 to about800 mg prior to, during, or after the occurrence of the adverse effectassociated with the administration of an anti-cancer drug to a patient.In a particular embodiment, a selective cytokine inhibitory drug of theinvention is administered in combination with specific agents such asheparin, aspirin, coumadin, or G-CSF to avoid adverse effects that areassociated with anti-cancer drugs such as but not limited to neutropeniaor thrombocytopenia.

In one embodiment, a selective cytokine inhibitory drug of the inventioncan be administered to patients with diseases and disorders associatedwith, or characterized by, undesired angiogenesis in combination withadditional active ingredients including but not limited to anti-cancerdrugs, anti-inflammatories, antihistamines, antibiotics, and steroids.

In another embodiment, this invention encompasses a method of treating,preventing and/or managing cancer, which comprises administering aselective cytokine inhibitory drug of the invention, or apharmaceutically acceptable salt, solvate, hydrate, stereoisomer,clathrate, or prodrug thereof, in conjunction with (e.g. before, during,or after) conventional therapy including, but not limited to, surgery,immunotherapy, biological therapy, radiation therapy, or other non-drugbased therapy presently used to treat, prevent or manage cancer. Thecombined use of the selective cytokine inhibitory drugs of the inventionand conventional therapy may provide a unique treatment regimen that isunexpectedly effective in certain patients. Without being limited bytheory, it is believed that selective cytokine inhibitory drugs of theinvention may provide additive or synergistic effects when givenconcurrently with conventional therapy.

As discussed elsewhere herein, the invention encompasses a method ofreducing, treating and/or preventing adverse or undesired effectsassociated with conventional therapy including, but not limited to,surgery, chemotherapy, radiation therapy, hormonal therapy, biologicaltherapy and immunotherapy. One or more selective cytokine inhibitorydrugs of the invention and other active ingredient can be administeredto a patient prior to, during, or after the occurrence of the adverseeffect associated with conventional therapy.

In one embodiment, a selective cytokine inhibitory drug of the inventioncan be administered in an amount of from about 1 to about 5,000 mg, fromabout 10 to about 2,500 mg, from about 25 to about 2,500 mg, from about100 to about 1,200 mg, or from about 100 to about 800 mg orally anddaily alone, or in combination with a second active agent disclosedherein (see, e.g., section 4.2), prior to, during, or after the use ofconventional therapy.

In a specific embodiment of this method, a selective cytokine inhibitorydrug of the invention and doxetaxol are administered to patients withnon-small cell lung cancer who were previously treated with carbo/VP 16and radiotherapy.

4.3.2 Use with Transplantation Therapy

Compounds of the invention can be used to reduce the risk of GraftVersus Host Disease (GVHD). Therefore, the invention encompasses amethod of treating, preventing and/or managing cancer, which comprisesadministering the selective cytokine inhibitory drug of the invention,or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer,clathrate, or prodrug thereof, in conjunction with transplantationtherapy.

As those of ordinary skill in the art are aware, the treatment of canceris often based on the stages and mechanism of the disease. For example,as inevitable leukemic transformation develops in certain stages ofcancer, transplantation of peripheral blood stem cells, hematopoieticstem cell preparation or bone marrow may be necessary. The combined useof the selective cytokine inhibitory drug of the invention andtransplantation therapy provides a unique and unexpected synergism. Inparticular, a selective cytokine inhibitory drug of the inventionexhibits activity that may provide additive or synergistic effects whengiven concurrently with transplantation therapy in patients with cancer.

A selective cytokine inhibitory drug of the invention can work incombination with transplantation therapy reducing complicationsassociated with the invasive procedure of transplantation and risk ofGVHD. This invention encompasses a method of treating, preventing and/ormanaging cancer which comprises administering to a patient (e.g., ahuman) a selective cytokine inhibitory drug of the invention, or apharmaceutically acceptable salt, solvate, hydrate, stereoisomer,clathrate, or prodrug thereof, before, during, or after thetransplantation of umbilical cord blood, placental blood, peripheralblood stem cell, hematopoietic stem cell preparation or bone marrow.Examples of stem cells suitable for use in the methods of the inventionare disclosed in U.S. provisional patent application No. 60/372,348,filed Apr. 12, 2002 by R. Hariri et al., the entirety of which isincorporated herein by reference.

In one embodiment of this method, a selective cytokine inhibitory drugof the invention is administered to patients with multiple myelomabefore, during, or after the transplantation of autologous peripheralblood progenitor cell.

In another embodiment, a selective cytokine inhibitory drug isadministered to patients with relapsing multiple myeloma after the stemcell transplantation.

In another embodiment, a selective cytokine inhibitory drug andprednisone are administered as maintenance therapy to patients withmultiple myeloma following the transplantation of autologous stem cell.

In another embodiment, a selective cytokine inhibitory drug anddexamethasone are administered as salvage therapy for low risk posttransplantation to patients with multiple myeloma.

In another embodiment, a selective cytokine inhibitory drug anddexamethasone are administered as maintenance therapy to patients withmultiple myeloma following the transplantation of autologous bonemarrow.

In another embodiment, a selective cytokine inhibitory drug isadministered following the administration of high dose of melphalan andthe transplantation of autologous stem cell to patients withchemotherapy responsive multiple myeloma.

In another embodiment, a selective cytokine inhibitory drug and PEGINTRO-A are administered as maintenance therapy to patients withmultiple myeloma following the transplantation of autologousCD34-selected peripheral stem cell.

In another embodiment, a selective cytokine inhibitory drug isadministered with post transplant consolidation chemotherapy to patientswith newly diagnosed multiple myeloma to evaluate anti-angiogenesis.

In another embodiment, a selective cytokine inhibitory drug anddexamethasone are administered as maintenance therapy after DCEPconsolidation, following the treatment with high dose of melphalan andthe transplantation of peripheral blood stem cell to 65 years of age orolder patients with multiple myeloma.

4.3.3 Cycling Therapy

In certain embodiments, the prophylactic or therapeutic agents of theinvention are cyclically administered to a patient. Cycling therapyinvolves the administration of an active agent for a period of time,followed by a rest for a period of time, and repeating this sequentialadministration. Cycling therapy can reduce the development of resistanceto one or more of the therapies, avoid or reduce the side effects of oneof the therapies, and/or improves the efficacy of the treatment.

Consequently, in one specific embodiment of the invention, a selectivecytokine inhibitory drug of the invention is administered daily in asingle or divided doses in a four to six week cycle with a rest periodof about a week or two weeks. The invention further allows thefrequency, number, and length of dosing cycles to be increased. Thus,another specific embodiment of the invention encompasses theadministration of a selective cytokine inhibitory drug of the inventionfor more cycles than are typical when it is administered alone. In yetanother specific embodiment of the invention, a selective cytokineinhibitory drug of the invention is administered for a greater number ofcycles that would typically cause dose-limiting toxicity in a patient towhom a second active ingredient is not also being administered.

In one embodiment, a selective cytokine inhibitory drug of the inventionis administered daily and continuously for three or four weeks at a doseof from about 1 to about 5,000 mg/d followed by a break of one or twoweeks.3-(3,4-Dimethoxy-phenyl)-3-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionamideis preferably administered daily and continuously at an initial dose of1 to 5 mg/d with dose escalation (every week) by 10 to 100 mg/d to amaximum dose of 5,000 mg/d for as long as therapy is tolerated. In aparticular embodiment, the compound is administered in an amount ofabout 400, 800, or 1,200 mg/day, preferably in an amount of about 800mg/day for three to four weeks, followed by one week or two weeks ofrest in a four or six week cycle.

In one embodiment of the invention, a selective cytokine inhibitory drugof the invention and a second active ingredient are administered orally,with administration of a selective cytokine inhibitory drug of theinvention occurring 30 to 60 minutes prior to a second activeingredient, during a cycle of four to six weeks. In another embodimentof the invention, the combination of a selective cytokine inhibitorydrug of the invention and a second active ingredient is administered byintravenous infusion over about 90 minutes every cycle. In a specificembodiment, one cycle comprises the administration of from about 400 toabout 800 mg/day of3-(3,4-dimethoxy-phenyl)-3-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionamideand from about 50 to about 200 mg/m²/day of a second active ingredientdaily for 3 to 4 weeks and then one or two weeks of rest. In anotherspecific embodiment, each cycle comprises the administration of fromabout 200 to about 400 mg/day of3-(3,4-dimethoxy-phenyl)-3-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionamideand from about 50 to about 200 mg/m²/day of a second active ingredientfor three to four weeks followed by one or two weeks of rest. Typically,the number of cycles during which the combinatorial treatment isadministered to a patient will be from about one to about 24 cycles,more typically from about two to about 16 cycles, and even moretypically from about four to about eight cycles.

4.4 Pharmaceutical Compositions

Pharmaceutical compositions can be used in the preparation ofindividual, single unit dosage forms. Pharmaceutical compositions anddosage forms of the invention comprise a selective cytokine inhibitorydrug of the invention, or a pharmaceutically acceptable salt, solvate,hydrate, stereoisomer, clathrate, or prodrug thereof. Pharmaceuticalcompositions and dosage forms of the invention can further comprise oneor more excipients.

Pharmaceutical compositions and dosage forms of the invention can alsocomprise one or more additional active ingredients. Consequently,pharmaceutical compositions and dosage forms of the invention comprisethe active ingredients disclosed herein (e.g., a selective cytokineinhibitory drug and a second active agent). Examples of optional second,or additional, active ingredients are disclosed herein (see, e.g.,section 4.2).

Single unit dosage forms of the invention are suitable for oral, mucosal(e.g., nasal, sublingual, vaginal, buccal, or rectal), parenteral (e.g.,subcutaneous, intravenous, bolus injection, intramuscular, orintraarterial), topical (e.g., eye drops or other ophthalmicpreparations), transdermal or transcutaneous administration to apatient. Examples of dosage forms include, but are not limited to:tablets; caplets; capsules, such as soft elastic gelatin capsules;cachets; troches; lozenges; dispersions; suppositories; powders;aerosols (e.g., nasal sprays or inhalers); gels; liquid dosage formssuitable for oral or mucosal administration to a patient, includingsuspensions (e.g., aqueous or non-aqueous liquid suspensions,oil-in-water emulsions, or a water-in-oil liquid emulsions), solutions,and elixirs; liquid dosage forms suitable for parenteral administrationto a patient; eye drops or other ophthalmic preparations suitable fortopical administration; and sterile solids (e.g., crystalline oramorphous solids) that can be reconstituted to provide liquid dosageforms suitable for parenteral administration to a patient.

The composition, shape, and type of dosage forms of the invention willtypically vary depending on their use. For example, a dosage form usedin the acute treatment of a disease may contain larger amounts of one ormore of the active ingredients it comprises than a dosage form used inthe chronic treatment of the same disease. Similarly, a parenteraldosage form may contain smaller amounts of one or more of the activeingredients it comprises than an oral dosage form used to treat the samedisease. These and other ways in which specific dosage forms encompassedby this invention will vary from one another will be readily apparent tothose skilled in the art. See, e.g., Remington's PharmaceuticalSciences, 18th ed., Mack Publishing, Easton Pa. (1990).

Typical pharmaceutical compositions and dosage forms comprise one ormore excipients. Suitable excipients are well known to those skilled inthe art of pharmacy, and non-limiting examples of suitable excipientsare provided herein. Whether a particular excipient is suitable forincorporation into a pharmaceutical composition or dosage form dependson a variety of factors well known in the art including, but not limitedto, the way in which the dosage form will be administered to a patient.For example, oral dosage forms such as tablets may contain excipientsnot suited for use in parenteral dosage forms. The suitability of aparticular excipient may also depend on the specific active ingredientsin the dosage form. For example, the decomposition of some activeingredients may be accelerated by some excipients such as lactose, orwhen exposed to water. Active ingredients that comprise primary orsecondary amines are particularly susceptible to such accelerateddecomposition. Consequently, this invention encompasses pharmaceuticalcompositions and dosage forms that contain little, if any, lactose othermono- or di-saccharides. As used herein, the term “lactose-free” meansthat the amount of lactose present, if any, is insufficient tosubstantially increase the degradation rate of an active ingredient.

Lactose-free compositions of the invention can comprise excipients thatare well known in the art and are listed, for example, in the U.S.Pharmacopeia (USP) 25-NF20 (2002). In general, lactose-free compositionscomprise active ingredients, a binder/filler, and a lubricant inpharmaceutically compatible and pharmaceutically acceptable amounts.Preferred lactose-free dosage forms comprise active ingredients,microcrystalline cellulose, pre-gelatinized starch, and magnesiumstearate.

This invention further encompasses anhydrous pharmaceutical compositionsand dosage forms comprising active ingredients, since water canfacilitate the degradation of some compounds. For example, the additionof water (e.g., 5%) is widely accepted in the pharmaceutical arts as ameans of simulating long-term storage in order to determinecharacteristics such as shelf-life or the stability of formulations overtime. See, e.g., Jens T. Carstensen, Drug Stability: Principles &Practice, 2d. Ed., Marcel Dekker, NY, N.Y., 1995, pp. 379-80. In effect,water and heat accelerate the decomposition of some compounds. Thus, theeffect of water on a formulation can be of great significance sincemoisture and/or humidity are commonly encountered during manufacture,handling, packaging, storage, shipment, and use of formulations.

Anhydrous pharmaceutical compositions and dosage forms of the inventioncan be prepared using anhydrous or low moisture containing ingredientsand low moisture or low humidity conditions. Pharmaceutical compositionsand dosage forms that comprise lactose and at least one activeingredient that comprises a primary or secondary amine are preferablyanhydrous if substantial contact with moisture and/or humidity duringmanufacturing, packaging, and/or storage is expected.

An anhydrous pharmaceutical composition should be prepared and storedsuch that its anhydrous nature is maintained. Accordingly, anhydrouscompositions are preferably packaged using materials known to preventexposure to water such that they can be included in suitable formularykits. Examples of suitable packaging include, but are not limited to,hermetically sealed foils, plastics, unit dose containers (e.g., vials),blister packs, and strip packs.

The invention further encompasses pharmaceutical compositions and dosageforms that comprise one or more compounds that reduce the rate by whichan active ingredient will decompose. Such compounds, which are referredto herein as “stabilizers,” include, but are not limited to,antioxidants such as ascorbic acid, pH buffers, or salt buffers.

Like the amounts and types of excipients, the amounts and specific typesof active ingredients in a dosage form may differ depending on factorssuch as, but not limited to, the route by which it is to be administeredto patients. However, typical dosage forms of the invention comprise aselective cytokine inhibitory drug of the invention or apharmaceutically acceptable salt, solvate, hydrate, stereoisomer,clathrate, or prodrug thereof in an amount of from about 0.10 to about150 mg. Typical dosage forms comprise a selective cytokine inhibitorydrug of the invention or a pharmaceutically acceptable salt, solvate,hydrate, stereoisomer, clathrate, or prodrug thereof in an amount ofabout 0.1, 1, 2, 5, 7.5, 10, 12.5, 15, 17.5, 20, 25, 50, 100, 150 or 200mg. In a particular embodiment, a preferred dosage form comprises4-(amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione (Actimid™) inan amount of about 1, 2, 5, 10, 25 or 50 mg. In a specific embodiment, apreferred dosage form comprises3-(3,4-dimethoxy-phenyl)-3-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionamidein an amount of about 5, 10, 25 or 50 mg. Typical dosage forms comprisethe second active ingredient in an amount of 1 to about 1000 mg, fromabout 5 to about 500 mg, from about 10 to about 350 mg, or from about 50to about 200 mg. Of course, the specific amount of the anti-cancer drugwill depend on the specific agent used, the type of cancer being treatedor managed, and the amount(s) of a selective cytokine inhibitory drug ofthe invention and any optional additional active agents concurrentlyadministered to the patient.

4.4.1 Oral Dosage Forms

Pharmaceutical compositions of the invention that are suitable for oraladministration can be presented as discrete dosage forms, such as, butare not limited to, tablets (e.g., chewable tablets), caplets, capsules,and liquids (e.g., flavored syrups). Such dosage forms containpredetermined amounts of active ingredients, and may be prepared bymethods of pharmacy well known to those skilled in the art. Seegenerally, Remington's Pharmaceutical Sciences, 18th ed., MackPublishing, Easton Pa. (1990).

Typical oral dosage forms of the invention are prepared by combining theactive ingredients in an intimate admixture with at least one excipientaccording to conventional pharmaceutical compounding techniques.Excipients can take a wide variety of forms depending on the form ofpreparation desired for administration. For example, excipients suitablefor use in oral liquid or aerosol dosage forms include, but are notlimited to, water, glycols, oils, alcohols, flavoring agents,preservatives, and coloring agents. Examples of excipients suitable foruse in solid oral dosage forms (e.g., powders, tablets, capsules, andcaplets) include, but are not limited to, starches, sugars,micro-crystalline cellulose, diluents, granulating agents, lubricants,binders, and disintegrating agents.

Because of their ease of administration, tablets and capsules representthe most advantageous oral dosage unit forms, in which case solidexcipients are employed. If desired, tablets can be coated by standardaqueous or nonaqueous techniques. Such dosage forms can be prepared byany of the methods of pharmacy. In general, pharmaceutical compositionsand dosage forms are prepared by uniformly and intimately admixing theactive ingredients with liquid carriers, finely divided-solid carriers,or both, and then shaping the product into the desired presentation ifnecessary.

For example, a tablet can be prepared by compression or molding.Compressed tablets can be prepared by compressing in a suitable machinethe active ingredients in a free-flowing form such as powder orgranules, optionally mixed with an excipient. Molded tablets can be madeby molding in a suitable machine a mixture of the powdered compoundmoistened with an inert liquid diluent.

Examples of excipients that can be used in oral dosage forms of theinvention include, but are not limited to, binders, fillers,disintegrants, and lubricants. Binders suitable for use inpharmaceutical compositions and dosage forms include, but are notlimited to, corn starch, potato starch, or other starches, gelatin,natural and synthetic gums such as acacia, sodium alginate, alginicacid, other alginates, powdered tragacanth, guar gum, cellulose and itsderivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethylcellulose calcium, sodium carboxymethyl cellulose), polyvinylpyrrolidone, methyl cellulose, pre-gelatinized starch, hydroxypropylmethyl cellulose, (e.g. Nos. 2208, 2906, 2910), microcrystallinecellulose, and mixtures thereof.

Suitable forms of microcrystalline cellulose include, but are notlimited to, the materials sold as AVICEL-PH-101, AVICEL-PH-103 AVICELRC-581, AVICEL-PH-105 (available from FMC Corporation, American ViscoseDivision, Avicel Sales, Marcus Hook, Pa.), and mixtures thereof. Anspecific binder is a mixture of microcrystalline cellulose and sodiumcarboxymethyl cellulose sold as AVICEL RC-581. Suitable anhydrous or lowmoisture excipients or additives include AVICEL-PH-103™ and Starch 1500LM.

Examples of fillers suitable for use in the pharmaceutical compositionsand dosage forms disclosed herein include, but are not limited to, talc,calcium carbonate (e.g., granules or powder), microcrystallinecellulose, powdered cellulose, dextrates, kaolin, mannitol, silicicacid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.The binder or filler in pharmaceutical compositions of the invention istypically present in from about 50 to about 99 weight percent of thepharmaceutical composition or dosage form.

Disintegrants are used in the compositions of the invention to providetablets that disintegrate when exposed to an aqueous environment.Tablets that contain too much disintegrant may disintegrate in storage,while those that contain too little may not disintegrate at a desiredrate or under the desired conditions. Thus, a sufficient amount ofdisintegrant that is neither too much nor too little to detrimentallyalter the release of the active ingredients should be used to form solidoral dosage forms of the invention. The amount of disintegrant usedvaries based upon the type of formulation, and is readily discernible tothose of ordinary skill in the art. Typical pharmaceutical compositionscomprise from about 0.5 to about 15 weight percent of disintegrant,preferably from about 1 to about 5 weight percent of disintegrant.

Disintegrants that can be used in pharmaceutical compositions and dosageforms of the invention include, but are not limited to, agar-agar,alginic acid, calcium carbonate, microcrystalline cellulose,croscarmellose sodium, crospovidone, polacrilin potassium, sodium starchglycolate, potato or tapioca starch, other starches, pre-gelatinizedstarch, other starches, clays, other algins, other celluloses, gums, andmixtures thereof.

Lubricants that can be used in pharmaceutical compositions and dosageforms of the invention include, but are not limited to, calciumstearate, magnesium stearate, mineral oil, light mineral oil, glycerin,sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid,sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanutoil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, andsoybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, andmixtures thereof. Additional lubricants include, for example, a syloidsilica gel (AEROSIL200, manufactured by W.R. Grace Co. of Baltimore,Md.), a coagulated aerosol of synthetic silica (marketed by Degussa Co.of Plano, Tex.), CAB-O-SIL (a pyrogenic silicon dioxide product sold byCabot Co. of Boston, Mass.), and mixtures thereof. If used at all,lubricants are typically used in an amount of less than about 1 weightpercent of the pharmaceutical compositions or dosage forms into whichthey are incorporated.

A preferred solid oral dosage form of the invention comprises aselective cytokine inhibitory drug of the invention, anhydrous lactose,microcrystalline cellulose, polyvinylpyrrolidone, stearic acid,colloidal anhydrous silica, and gelatin.

4.4.2 Delayed Release Dosage Forms

Active ingredients of the invention can be administered by controlledrelease means or by delivery devices that are well known to those ofordinary skill in the art. Examples include, but are not limited to,those described in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809;3,598,123; and 4,008,719, 5,674,533, 5,059,595, 5,591,767, 5,120,548,5,073,543, 5,639,476, 5,354,556, and 5,733,566, each of which isincorporated herein by reference. Such dosage forms can be used toprovide slow or controlled-release of one or more active ingredientsusing, for example, hydropropylmethyl cellulose, other polymer matrices,gels, permeable membranes, osmotic systems, multilayer coatings,microparticles, liposomes, microspheres, or a combination thereof toprovide the desired release profile in varying proportions. Suitablecontrolled-release formulations known to those of ordinary skill in theart, including those described herein, can be readily selected for usewith the active ingredients of the invention. The invention thusencompasses single unit dosage forms suitable for oral administrationsuch as, but not limited to, tablets, capsules, gelcaps, and capletsthat are adapted for controlled-release.

All controlled-release pharmaceutical products have a common goal ofimproving drug therapy over that achieved by their non-controlledcounterparts. Ideally, the use of an optimally designedcontrolled-release preparation in medical treatment is characterized bya minimum of drug substance being employed to cure or control thecondition in a minimum amount of time. Advantages of controlled-releaseformulations include extended activity of the drug, reduced dosagefrequency, and increased patient compliance. In addition,controlled-release formulations can be used to affect the time of onsetof action or other characteristics, such as blood levels of the drug,and can thus affect the occurrence of side (e.g., adverse) effects.

Most controlled-release formulations are designed to initially releasean amount of drug (active ingredient) that promptly produces the desiredtherapeutic effect, and gradually and continually release of otheramounts of drug to maintain this level of therapeutic or prophylacticeffect over an extended period of time. In order to maintain thisconstant level of drug in the body, the drug must be released from thedosage form at a rate that will replace the amount of drug beingmetabolized and excreted from the body. Controlled-release of an activeingredient can be stimulated by various conditions including, but notlimited to, pH, temperature, enzymes, water, or other physiologicalconditions or compounds.

4.4.3 Parenteral Dosage Forms

Parenteral dosage forms can be administered to patients by variousroutes including, but not limited to, subcutaneous, intravenous(including bolus injection), intramuscular, and intraarterial. Becausetheir administration typically bypasses patients' natural defensesagainst contaminants, parenteral dosage forms are preferably sterile orcapable of being sterilized prior to administration to a patient.Examples of parenteral dosage forms include, but are not limited to,solutions ready for injection, dry products ready to be dissolved orsuspended in a pharmaceutically acceptable vehicle for injection,suspensions ready for injection, and emulsions.

Suitable vehicles that can be used to provide parenteral dosage forms ofthe invention are well known to those skilled in the art. Examplesinclude, but are not limited to: Water for Injection USP; aqueousvehicles such as, but not limited to, Sodium Chloride Injection,Ringer's Injection, Dextrose Injection, Dextrose and Sodium ChlorideInjection, and Lactated Ringer's Injection; water-miscible vehicles suchas, but not limited to, ethyl alcohol, polyethylene glycol, andpolypropylene glycol; and non-aqueous vehicles such as, but not limitedto, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate,isopropyl myristate, and benzyl benzoate.

Compounds that increase the solubility of one or more of the activeingredients disclosed herein can also be incorporated into theparenteral dosage forms of the invention. For example, cyclodextrin andits derivatives can be used to increase the solubility of a selectivecytokine inhibitory drug of the invention and its derivatives. See, e.g.U.S. Pat. No. 5,134,127, which is incorporated herein by reference.

4.4.4 Topical and Mucosal Dosage Forms

Topical and mucosal dosage forms of the invention include, but are notlimited to, sprays, aerosols, solutions, emulsions, suspensions, eyedrops or other ophthalmic preparations, or other forms known to one ofskill in the art. See, e.g., Remington's Pharmaceutical Sciences,16^(th) and 18^(th) eds., Mack Publishing, Easton Pa. (1980 & 1990); andIntroduction to Pharmaceutical Dosage Forms, 4th ed., Lea & Febiger,Philadelphia (1985). Dosage forms suitable for treating mucosal tissueswithin the oral cavity can be formulated as mouthwashes or as oral gels.

Suitable excipients (e.g., carriers and diluents) and other materialsthat can be used to provide topical and mucosal dosage forms encompassedby this invention are well known to those skilled in the pharmaceuticalarts, and depend on the particular tissue to which a givenpharmaceutical composition or dosage form will be applied. With thatfact in mind, typical excipients include, but are not limited to, water,acetone, ethanol, ethylene glycol, propylene glycol, butane-1,3-diol,isopropyl myristate, isopropyl palmitate, mineral oil, and mixturesthereof to form solutions, emulsions or gels, which are non-toxic andpharmaceutically acceptable. Moisturizers or humectants can also beadded to pharmaceutical compositions and dosage forms if desired.Examples of such additional ingredients are well known in the art. See,e.g., Remington's Pharmaceutical Sciences, 16^(th) and 18^(th) eds.,Mack Publishing, Easton Pa. (1980 & 1990).

The pH of a pharmaceutical composition or dosage form may also beadjusted to improve delivery of one or more active ingredients.Similarly, the polarity of a solvent carrier, its ionic strength, ortonicity can be adjusted to improve delivery. Compounds such asstearates can also be added to pharmaceutical compositions or dosageforms to advantageously alter the hydrophilicity or lipophilicity of oneor more active ingredients so as to improve delivery. In this regard,stearates can serve as a lipid vehicle for the formulation, as anemulsifying agent or surfactant, and as a delivery-enhancing orpenetration-enhancing agent. Different salts, hydrates or solvates ofthe active ingredients can be used to further adjust the properties ofthe resulting composition.

4.4.5 Kits

Typically, active ingredients of the invention are preferably notadministered to a patient at the same time or by the same route ofadministration. This invention therefore encompasses kits which, whenused by the medical practitioner, can simplify the administration ofappropriate amounts of active ingredients to a patient.

A typical kit of the invention comprises a dosage form of a selectivecytokine inhibitory drug of the invention, or a pharmaceuticallyacceptable salt salt, solvate, hydrate, stereoisomer, prodrug, orclathrate thereof. Kits encompassed by this invention can furthercomprise additional active ingredients such as oblimersen (Genasense®),melphalan, G-CSF, GM-CSF, EPO, topotecan, dacarbazine, irinotecan,taxotere, IFN, COX-2 inhibitor, pentoxifylline, ciprofloxacin,dexamethasone, IL2, IL8, IL18, Ara-C, vinorelbine, isotretinoin, 13cis-retinoic acid, or a pharmacologically active mutant or derivativethereof, or a combination thereof. Examples of the additional activeingredients include, but are not limited to, those disclosed herein(see, e.g., section 5.2).

Kits of the invention can further comprise devices that are used toadminister the active ingredients. Examples of such devices include, butare not limited to, syringes, drip bags, patches, and inhalers.

Kits of the invention can further comprise cells or blood fortransplantation as well as pharmaceutically acceptable vehicles that canbe used to administer one or more active ingredients. For example, if anactive ingredient is provided in a solid form that must be reconstitutedfor parenteral administration, the kit can comprise a sealed containerof a suitable vehicle in which the active ingredient can be dissolved toform a particulate-free sterile solution that is suitable for parenteraladministration. Examples of pharmaceutically acceptable vehiclesinclude, but are not limited to: Water for Injection USP; aqueousvehicles such as, but not limited to, Sodium Chloride Injection,Ringer's Injection, Dextrose Injection, Dextrose and Sodium ChlorideInjection, and Lactated Ringer's Injection; water-miscible vehicles suchas, but not limited to, ethyl alcohol, polyethylene glycol, andpolypropylene glycol; and non-aqueous vehicles such as, but not limitedto, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate,isopropyl myristate, and benzyl benzoate.

5. EXAMPLES

Certain embodiments of the invention are illustrated by the followingnon-limiting examples.

5.1 Modulation of Cytokine Production

A series of non-clinical pharmacology and toxicology studies have beenperformed to support the clinical evaluation of a selective cytokineinhibitory drug of the invention in human subjects. These studies wereperformed in accordance with internationally recognized guidelines forstudy design and in compliance with the requirements of Good LaboratoryPractice (GLP), unless otherwise noted.

In a specific embodiment, the pharmacological properties of3-(3,4-dimethoxy-phenyl)-3-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionamideare characterized in in vitro studies. Studies examine the effects ofthe compound on the production of various cytokines. Inhibition of TNF-αproduction following LPS-stimulation of human PBMC and human whole bloodby the compound is investigated in vitro. In vitro studies suggest apharmacological activity profile for3-(3,4-dimethoxy-phenyl)-3-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionamideis five to fifty times more potent than thalidomide. The pharmacologicaleffects of3-(3,4-dimethoxy-phenyl)-3-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionamidemay derive from its action as an inhibitor of the generation ofinflammatory cytokines.

5.2 Inhibition of MM Cell Proliferation

The ability of a selective cytokine inhibitory drug to effect theproliferation of multiple myeloma (MM) cell lines is investigated in anin vitro study. Uptake [³H]-thymidine by different MM cell lines (MM.1S,Hs Sultan, U266 and RPMI-8226) is measured as an indicator of cellproliferation. Cells are incubated in the presence of compound for 48hours; [³H]-thymidine is included for the last 8 hours of the incubationperiod. In a specific embodiment,3-(3,4-dimethoxy-phenyl)-3-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionamideis added to MM.1S and Hs Sultan cells. The uptake [³H]-thymidine bydifferent MM cell lines is measured.

5.3 In Vivo LPS-Induced TNF-α Production Assay

Male CD rats procured from Charles River Laboratories at seven weeks ofage are allowed to acclimate for one week prior to use. A lateral tailvein is cannulated percutaneously with a 22-gage over-the-needlecatheter under brief isoflurane anesthesia. Rats are administered aselective cytokine inhibitory drug of the invention either byintravenous injection via the tail vein catheter or oral gavage 15 to180 min prior to injection of 0.05 mg/kg LPS (E. Coli 055:B5). Cathetersare flushed with 2.5 ml/kg of normal injectable saline. Blood iscollected via cardiac puncture 90 minutes after LPS challenge. Plasma isprepared using lithium heparin separation tubes and frozen at −80° C.until analyzed. TNF-α levels are determined using a rat specific TNF-αELISA kit (Busywork). The ED₅₀ values are calculated as the dose of theselective cytokine inhibitory drug of the invention at which the TNF-αproduction is reduced to 50% of the control value.

5.4 Toxicology Studies

The effects of3-(3,4-dimethoxy-phenyl)-3-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionamideon cardiovascular and respiratory function are investigated inanesthetized dogs. Two groups of Beagle dogs (2/sex/group) are used. Onegroup receives three doses of vehicle only and the other receives threeascending doses of the compound (200, 400, and 800 mg/kg). In all cases,doses of the compound or vehicle are successively administered viainfusion through the jugular vein separated by intervals of at least 30minutes.

The cardiovascular and respiratory changes induced by3-(3,4-diethoxy-phenyl)-3-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionamideare minimal at all doses when compared to the vehicle control group. Theonly statistically significant difference between the vehicle andtreatment groups is a small increase in arterial blood pressurefollowing administration of the low dose of3-(3,4-dimethoxy-phenyl)-3-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionamide.This effect lasts approximately 15 minutes and is not seen at higherdoses. Deviations in femoral blood flow, respiratory parameters, and Qtcinterval are common to both the control and treated groups and are notconsidered treatment-related.

5.5 Cycling Therapy in Patients

In a specific embodiment, a selective cytokine inhibitory drug of theinvention are cyclically administered to patients with cancer. Cyclingtherapy involves the administration of a first agent for a period oftime, followed by a rest for a period of time and repeating thissequential administration. Cycling therapy can reduce the development ofresistance to one or more of the therapies, avoid or reduce the sideeffects of one of the therapies, and/or improves the efficacy of thetreatment.

In a specific embodiment, prophylactic or therapeutic agents areadministered in a cycle of about four to six weeks, about once or twiceevery day. One cycle can comprise the administration of a therapeutic onprophylactic agent for three to four weeks and at least one week or twoweeks of rest. The number of cycles administered is from about one toabout 24 cycles, more typically from about two to about 16 cycles, andmore typically from about four to about eight cycles.

For example, in a cycle of four weeks, on day 1, the administration of800 mg/d of3-(3,4-dimethoxy-phenyl)-3-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionamideis started. On day 22, the administration of the compound is stopped fora week of rest. On day 29, the administration of 800 mg/d of thecompound is begun.

5.6 Clinical Studies in Patients with Relapsed Multiple Myeloma

Patients with relapsed and refractory Dune-Salmon stage III multiplemyeloma, who have either failed at least three previous regimens orpresented with poor performance status, neutropenia or thrombocytopenia,are treated with up to four cycles of combination melphalan (50 mgintravenously), a selective cytokine inhibitory drug of the invention(about 1 to 5,000 mg orally daily), and dexamethasone (40 mg/day orallyon days 1 to 4) every four to six weeks. Maintenance treatmentconsisting of daily a selective cytokine inhibitory drug of theinvention and monthly dexamethasone are continued until the diseaseprogression. The therapy comprising the administration of a selectivecytokine inhibitory drug of the invention in combination with melphalanand dexamethasone is highly active and generally tolerated in heavilypretreated multiple myeloma patients whose prognosis is otherwise poor.

The embodiments of the invention described above are intended to bemerely exemplary, and those skilled in the art will recognize, or willbe able to ascertain using no more than routine experimentation,numerous equivalents of specific compounds, materials, and procedures.All such equivalents are considered to be within the scope of theinvention and are encompassed by the appended claims.

The embodiments of the invention described above are intended to bemerely exemplary, and those skilled in the art will recognize, or willbe able to ascertain using no more than routine experimentation,numerous equivalents of specific compounds, materials, and procedures.All such equivalents are considered to be within the scope of theinvention and are encompassed by the appended claims.

1. A method of treating, managing or preventing a specific cancer, whichcomprises administering to a patient in need of such treatment,management or prevention a therapeutically or prophylactically effectiveamount of a selective cytokine inhibitory drug, or a pharmaceuticallyacceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrugthereof.
 2. A method of treating, managing or preventing a specificcancer, which comprises administering to a patient in need of suchtreatment, management or prevention a therapeutically orprophylactically effective amount of a selective cytokine inhibitorydrug, or a pharmaceutically acceptable salt, solvate, hydrate,stereoisomer, clathrate, or prodrug thereof, and a therapeutically orprophylactically effective amount of a second active ingredient,radiation therapy, hormonal therapy, biological therapy orimmunotherapy.
 3. A method of treating, managing or preventing a diseaseassociated with undesired angiogenesis, which comprises administering toa patient in need of such treatment, management or prevention atherapeutically or prophylactically effective amount of a selectivecytokine inhibitory drug, or a pharmaceutically acceptable salt,solvate, hydrate, stereoisomer, clathrate, or prodrug thereof.
 4. Amethod of treating, managing or preventing a disease associated withundesired angiogenesis, which comprises administering to a patient inneed of such treatment, management or prevention a therapeutically orprophylactically effective amount of a selective cytokine inhibitorydrug, or a pharmaceutically acceptable salt, solvate, hydrate,stereoisomer, clathrate, or prodrug thereof, and a therapeutically orprophylactically effective amount of a second active ingredient.
 5. Themethod of claim 1, wherein the cancer is advanced malignancy,amyloidosis, neuroblastoma, meningioma, hemangiopericytoma, multiplebrain metastase, glioblastoma multiforms, glioblastoma, brain stemglioma, poor prognosis malignant brain tumor, malignant glioma,anaplastic astrocytoma, anaplastic oligodendroglioma, neuroendocrinetumor, rectal adenocarcinoma, Dukes C & D colorectal cancer,unresectable colorectal carcinoma, metastatic hepatocellular carcinoma,Kaposi's sarcoma, karotype acute myeloblastic leukemia, Hodgkin'slymphoma, non-Hodgkin's lymphoma, cutaneous T-Cell lymphoma, cutaneousB-Cell lymphoma, diffuse large B-Cell lymphoma, low grade follicularlymphoma, malignant melanoma, malignant mesothelioma, malignant pleuraleffusion mesothelioma syndrome, peritoneal carcinoma, papillary serouscarcinoma, gynecologic sarcoma, soft tissue sarcoma, scelroderma,cutaneous vasculitis, Langerhans cell histiocytosis, leiomyosarcoma,fibrodysplasia ossificans progressive, hormone refractory prostatecancer, resected high-risk soft tissue sarcoma, unrescectablehepatocellular carcinoma, Waldenstrom's macroglobulinemia, smolderingmyeloma, indolent myeloma, fallopian tube cancer, androgen independentprostate cancer, androgen dependent stage IV non-metastatic prostatecancer, hormone-insensitive prostate cancer, chemotherapy-insensitiveprostate cancer, papillary thyroid carcinoma, follicular thyroidcarcinoma, medullary thyroid carcinoma, or leiomyoma.
 6. The method ofclaim 2, wherein the cancer is advanced malignancy, amyloidosis, locallyadvanced bladder cancer, metastatic transitional cell bladder cancer,relapsed brain tumor, progressive brain tumor, neuroblastoma,meningioma, hemangiopericytoma, multiple brain metastase, glioblastomamultiforms, glioblastoma, brain stem glioma, poor prognosis malignantbrain tumor, malignant glioma, anaplastic astrocytoma, anaplasticoligodendroglioma, metastatic breast cancer, neuroendocrine tumor,rectal adenocarcinoma, Dukes C & D colorectal cancer, unresectablecolorectal carcinoma, metastatic hepatocellular carcinoma, Kaposi'ssarcoma, karotype acute myeloblastic leukemia, Hodgkin's lymphoma,non-Hodgkin's lymphoma, cutaneous T-Cell lymphoma, cutaneous B-Celllymphoma, diffuse large B-Cell lymphoma, low grade follicular lymphoma,malignant melanoma, malignant mesothelioma, stage IIIB non-small celllung cancer, malignant pleural effusion mesothelioma syndrome, multiplemyeloma, peritoneal carcinoma, papillary serous carcinoma, gynecologicsarcoma, soft tissue sarcoma, scelroderma, cutaneous vasculitis,Langerhans cell histiocytosis, leiomyosarcoma, fibrodysplasia ossificansprogressive, hormone refractory prostate cancer, resected high-risk softtissue sarcoma, unrescectable hepatocellular carcinoma, Waldenstrom'smacroglobulinemia, smoldering myeloma, indolent myeloma, fallopian tubecancer, androgen independent prostate cancer, androgen dependent stageIV non-metastatic prostate cancer, hormone-insensitive prostate cancer,chemotherapy-insensitive prostate cancer, papillary thyroid carcinoma,follicular thyroid carcinoma, medullary thyroid carcinoma, or leiomyoma.7. The method of claim 3 or 4, wherein the disease or disorder isdiabetic retinopathy, retinopathy of prematurity, corneal graftrejection, neovascular glaucoma, retrolental fibroplasia, proliferativevitreoretinopathy, trachoma, myopia, optic pits, epidemnickeratoconjunctivitis, atopic keratitis, superior limbic keratitis,pterygium keratitis sicca, sjogrens, acne rosacea, phylectenulosis,syphilis, lipid degeneration, bacterial ulcer, fungal ulcer, Herpessimplex infection, Herpes zoster infection, protozoan infection, Kaposisarcoma, Mooren ulcer, Terrien's marginal degeneration, mariginalkeratolysis, rheumatoid arthritis, systemic lupus, polyarteritis,trauma, Wegeners sarcoidosis, Scleritis, Steven's Johnson disease,periphigoid radial keratotomy, sickle cell anemia, sarcoid,pseudoxanthoma elasticum, Pagets disease, vein occlusion, arteryocclusion, carotid obstructive disease, chronic uveitis, chronicvitritis, Lyme's disease, Eales disease, Bechets disease, retinitis,choroiditis, presumed ocular histoplasmosis, Bests disease, Stargartsdisease, pars planitis, chronic retinal detachment, hyperviscositysyndromes, toxoplasmosis, sclerosing cholangitis, or rubeosis.
 8. Themethod of claim 2 or 4, wherein the second active ingredient ishematopoietic growth factor, cytokine, anti-cancer agent, antibiotic,cox-2 inhibitor, immunomodulatory agent, immunosuppressive agent,corticosteroid, or a pharmacologically active mutant or derivativethereof, or a combination thereof.
 9. The method of claim 8, wherein thesecond active ingredient is oblimersen, melphalan, G-CSF, GM-CSF, EPO,topotecan, pentoxifylline, taxotere, iritotecan, a COX-2 inhibitor,ciprofloxacin, dexamethasone, doxorubicin, vincristine, IL 2, IFN,dacarbazine, Ara-C, vinorelbine, isotretinoin, or a pharmaceuticallyacceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrugthereof, or a pharmacologically active mutant or derivative thereof, ora combination thereof.
 10. The method of one of claims 1-4, wherein theselective cytokine inhibitory drug is3-(3,4-dimethoxy-phenyl)-3-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionamide.11. The method of claim 10, wherein the selective cytokine inhibitorydrug is enantiomerically pure.
 12. The method of any one of claims 1-4,wherein the selective cytokine inhibitory drug is cyclopropanecarboxylicacid{2-[1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl-amide.13. The method of claim 12, wherein the selective cytokine inhibitorydrug is enantiomerically pure.
 14. The method of any one of claims 1-4,wherein the selective cytokine inhibitory drug is of formula (I):

wherein n has a value of 1, 2, or 3; R⁵ is o-phenylene, unsubstituted orsubstituted with 1 to 4 substituents each selected independently fromthe group consisting of nitro, cyano, trifluoromethyl, carbethoxy,carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy,hydroxy, amino, alkylamino, dialkylamino, acylamino, alkyl of 1 to 10carbon atoms, alkyl of 1 to 10 carbon atoms, and halo; R⁷ is (i) phenylor phenyl substituted with one or more substituents each selectedindependently of the other from the group consisting of nitro, cyano,trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl,carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl of 1 to 10 carbonatoms, alkoxy of 1 to 10 carbon atoms, and halo, (ii) benzylunsubstituted or substituted with 1 to 3 substituents selected from thegroup consisting of nitro, cyano, trifluoromethyl, carbothoxy,carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy,hydroxy, amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbonatoms, and halo, (iii) naphthyl, and (iv) benzyloxy; R¹² is —OH, alkoxyof 1 to 12 carbon atoms, or

R⁸ is hydrogen or alkyl of 1 to 10 carbon atoms; and R⁹ is hydrogen,alkyl of 1 to 10 carbon atoms, —COR¹⁰, or —SO₂R¹⁰, wherein R¹⁰ ishydrogen, alkyl of 1 to 10 carbon atoms, or phenyl.
 15. The method ofclaim 14, wherein the selective cytokine inhibitory drug isenantiomerically pure.
 16. The method of any one of claims 1-4, whereinthe selective cytokine inhibitory drug is of formula (II):

wherein each of R¹ and R², when taken independently of each other, ishydrogen, lower alkyl, or R¹ and R², when taken together with thedepicted carbon atoms to which each is bound, is o-phenylene,o-naphthylene, or cyclohexene-1,2-diyl, unsubstituted or substitutedwith 1 to 4 substituents each selected independently from the groupconsisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy,carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino,alkylamino, dialkylamino, acylamino, alkyl of 1 to 10 carbon atoms,alkoxy of 1 to 10 carbon atoms, and halo; R³ is phenyl substituted withfrom one to four substituents selected from the group consisting ofnitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy,acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl of 1 to 10carbon atoms, alkoxy of 1 to 10 carbon atoms, alkylthio of 1 to 10carbon atoms, benzyloxy, cycloalkoxy of 3 to 6 carbon atoms,C₄-C₆-cycloalkylidenemethyl, C₃-C₁₀-alkylidenemethyl, indanyloxy, andhalo; R⁴ is hydrogen, alkyl of 1 to 6 carbon atoms, phenyl, or benzyl;R^(4′) is hydrogen or alkyl of 1 to 6 carbon atoms; R⁵ is —CH₂—,—CH₂—CO—, —SO₂—, —S—, or —NHCO—; and n has a value of 0, 1, or
 2. 17.The method of claim 16, wherein the selective cytokine inhibitory drugis enantiomerically pure.
 18. A method of treating, preventing ormanaging a specific cancer, which comprises administering to a patientin need thereof a therapeutically or prophylactically effective amountof a selective cytokine inhibitory drug, or a pharmaceuticallyacceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrugthereof, before, during or after surgery directed at relieving, reducingor avoiding a symptom of a specific cancer in the patient.
 19. A methodof reducing or avoiding an adverse effect associated with theadministration of a second active ingredient in a patient suffering froma specific cancer, which comprises administering to a patient in needthereof a therapeutically or prophylactically effective amount of aselective cytokine inhibitory drug, or a pharmaceutically acceptablesalt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof. 20.A method of reducing or avoiding an adverse effect associated withradiation therapy, hormonal therapy, biological therapy, orimmunotherapy in a patient suffering from a specific cancer, whichcomprises administering to the patient in need thereof a therapeuticallyor prophylactically effective amount of a selective cytokine inhibitorydrug, or a pharmaceutically acceptable salt, solvate, hydrate,stereoisomer, clathrate, or prodrug thereof.
 21. A method of treating,preventing or managing a specific cancer which is refractory toconventional therapy, which comprises administering to the patient inneed thereof a therapeutically or prophylactically effective amount of aselective cytokine inhibitory drug, or a pharmaceutically acceptablesalt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof. 22.A method of treating, preventing or managing a specific cancer which isrefractory to conventional therapy, which comprises administering to thepatient in need thereof a therapeutically or prophylactically effectiveamount of a selective cytokine inhibitory drug, or a pharmaceuticallyacceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrugthereof, and a therapeutically or prophylactically effective amount of asecond active ingredient.
 23. A method of treating, preventing ormanaging a specific cancer, which comprises administering to a patientin need thereof a therapeutically or prophylactically effective amountof a selective cytokine inhibitory drug, or a pharmaceuticallyacceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrugthereof, and transplanting umbilical cord blood, placental blood,peripheral blood stem cell, hematopoietic stem cell preparation or bonemarrow in the patient.
 24. The method according to claim 23, wherein theselective cytokine inhibitory drug, or a pharmaceutically acceptablesalt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, isadministered prior to, during, or after transplanting umbilical cordblood, placental blood, peripheral blood stem cell, hematopoietic stemcell preparation or bone marrow in the patient.
 25. The method accordingto any one of claims 1-4, wherein the selective cytokine inhibitory drugis administered in an amount of from about 1 to about 5,000 mg per day.26. The method according to claim 2, wherein the selective cytokineinhibitory drug, or a pharmaceutically acceptable salt, solvate,hydrate, stereoisomer, clathrate, or prodrug thereof is administeredprior to, during, or after the administration of the second activeingredient, radiation therapy, hormonal therapy, biological therapy orimmunotherapy.
 27. A pharmaceutical composition comprising a selectivecytokine inhibitory drug, or a pharmaceutically acceptable salt,solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, and asecond active ingredient.
 28. The pharmaceutical composition of claim27, wherein the second active ingredient is hematopoietic growth factor,cytokine, anti-cancer agent, antibiotic, cox-2 inhibitor,immunomodulatory agent, immunosuppressive agent, corticosteroid, or apharmacologically active mutant or derivative thereof.
 29. Thepharmaceutical composition of claim 28, wherein the second activeingredient is oblimersen, melphalan, G-CSF, GM-CSF, EPO, a cox-2inhibitor, topotecan, pentoxifylline, ciprofloxacin, taxotere,iritotecan, dexamethasone, doxorubicin, vincristine, IL 2, IFN,dacarbazine, Ara-C, vinorelbine, isotretinoin, or a pharmaceuticallyacceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrugthereof, or a pharmacologically active mutant or derivative thereof. 30.A kit comprising: a pharmaceutical composition comprising a selectivecytokine inhibitory drug, or a pharmaceutically acceptable salt,solvate, hydrate, stereoisomer, clathrate, or prodrug thereof; and apharmaceutical composition comprising hematopoietic growth factor,cytokine, anti-cancer agent, antibiotic, a cox-2 inhibitor,immunomodulatory agent, immunosuppressive agent, corticosteroid, or apharmacologically active mutant or derivative thereof, or a combinationthereof.
 31. A kit comprising: a pharmaceutical composition comprising aselective cytokine inhibitory drug, or a pharmaceutically acceptablesalt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof; anda pharmaceutical composition comprising oblimersen, melphalan, G-CSF,GM-CSF, EPO, a cox-2 inhibitor, topotecan, pentoxifylline, taxotere,iritotecan, ciprofloxacin, dexamethasone, doxorubicin, vincristine, IL2, IFN, dacarbazine, Ara-C, vinorelbine, isotretinoin, or apharmaceutically acceptable salt, solvate, hydrate, stereoisomer,clathrate, or prodrug thereof, or a pharmacologically active mutant orderivative thereof, or a combination thereof.
 32. A kit comprising: apharmaceutical composition comprising a selective cytokine inhibitorydrug, or a pharmaceutically acceptable salt, solvate, hydrate,stereoisomer, clathrate, or prodrug thereof; and umbilical cord blood,placental blood, peripheral blood stem cell, hematopoietic stem cellpreparation or bone marrow.